Novel guanidinobenzamides

ABSTRACT

Compounds of formula IA and IB are new  
                 
 
     where the variables R 1  through R 10  have the values set forth herein. Such compounds have use in treating diseases such as obesity and type II diabetes, and may be provided as pharmaceutical formulations in conjunction with a pharmaceutically acceptable carrier.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/230,565 filed Aug. 31, 2000, and U.S. Provisional Application No.60/245,579 filed Nov. 6, 2000, the entire disclosures of which areincorporated herein by reference and for all purposes.

FIELD OF THE INVENTION

[0002] This invention relates to melanocortin-4 receptor (MC4-R)agonists and methods of their preparation. The invention also relates tomethods of treating melanocortin-4 receptor-mediated diseases, such asobesity or diabetes, by activating the melanocortin-4 receptor withcompounds provided herein.

BACKGROUND OF THE INVENTION

[0003] Melanocortins are peptide products resulting frompost-translational processing of pro-opiomelanocortin and are known tohave a broad array of physiological activities. The naturalmelanocortins include the different types of melanocyte stimulatinghormone (α-MSH, β-MSH, γ-MSH) and ACTH. Of these, α-MSH and ACTH areconsidered to be the main endogenous melanocortins.

[0004] The melanocortins mediate their effects through melanocortinreceptors (MC-Rs), a subfamily of G-protein coupled receptors. There areat least five different receptor subtypes (MC1-R to MC5-R). MC1-Rmediates pigmentation of the hair and skin. MC2-R mediates the effectsof ACTH on steroidogenesis in the adrenal gland. MC3-R and MC4-R arepredominantly expressed in the brain. MC5-R is considered to have a rolein the exocrine gland system.

[0005] The melanocortin-4 receptor (MC4-R) is a seven-transmembranereceptor. MC4-R may participate in modulating the flow of visual andsensory information, coordinate aspects of somatomotor control, and/orparticipate in the modulation of autonomic outflow to the heart. K. G.Mountjoy et al., Science, 257:1248-125 (1992). Significantly,inactivation of this receptor by gene targeting has resulted in micethat develop a maturity onset obesity syndrome associated withhyperphagia, hyperinsulinemia, and hyperglycemia. D. Husznar et al.,Cell, 88(1): 131-41 (1997). MC4-R has also been implicated in otherdisease states including erectile disorders, cardiovascular disorders,neuronal injuries or disorders, inflammation, fever, cognitivedisorders, and sexual behavior disorders. M. E. Hadley and C.Haskell-Luevano, The proopiomelanocortin system, Ann. N. Y. Acad. Sci.,885:1 (1999).

[0006] Furthermore, observations in connection with endogenous MCx-Rantagonists indicate that MC4-R is implicated in endogenous energyregulation. For example, an agouti protein is normally expressed in theskin and is an antagonist of the cutaneous MC receptor involved inpigmentation, MC1-R. M. M. Ollmann et al., Science, 278:135-138 (1997).However, overexpression of agouti protein in mice leads to a yellow coatcolor due to antagonism of MC1-R and increased food intake and bodyweight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry,36: 2084-2090 (1997); D. S. Lu et al., Nature, 371:799-802 (1994).Agouti related protein (AGRP), an agouti protein homologue, antagonizesMC4-R but not MC1-R. T. M. Fong et al., Biochem. Biophys. Res. Commun.237:629-631 (1997). Administration of AGRP in mice increases food intakeand causes obesity but does not alter pigmentation. M. Rossi et al.,Endocrinology, 139:4428-4431 (1998). Together, this research indicatesthat MC4-R participates in energy regulation, and therefore, identifiesthis receptor as a target for a rational drug design for the treatmentof obesity.

[0007] In connection with MC4-R and its uncovered role in the etiologyof obesity and food intake, the prior art includes reports of compoundsand compositions that act as agonists or antagonists of MC4-R. Asexamples, U.S. Pat. No. 6,060,589 describes polypeptides that arecapable of modulating signaling activity of melanocortin receptors.Also, U.S. Pat. Nos. 6,054,556 and 5,731,408 describe families ofagonists and antagonists for MC4-R receptors that are lactamheptapeptides having a cyclic structure. WO 01/10842 discloses MC4-Rbinding compounds having a multitude of structures and methods of usingsuch compounds to treat MC4-R associated disorders. Some of thecompounds described include amidino- and guanidino-containing arenes andheteroarenes.

[0008] Other guanidine-containing compounds having a variety ofbiological activities are also known in the prior art. For example, U.S.Pat. No. 4,732,916 issued to Satoh et al. discloses guanidine compoundsuseful as antiulcer agents; U.S. Pat. Nos. 4,874,864, 4,949,891, and4,948,901 issued to Schnur et al. and EP 0343 894 disclose guanidinocompounds useful as protease inhibitors and as anti-plasmin andanti-thrombin agents; and U.S. Pat. No. 5,352,704 issued to Okuyama etal. discloses a guanidino compound useful as an antiviral agent.Guanidine-containing compounds are also disclosed in other references.For example, U.S. Pat. No. 6,030,985 issued to Gentile et al. disclosesguanidine compounds useful for treating and preventing conditions inwhich inhibition of nitric oxide synthetase is beneficial such asstroke, schizophrenia, anxiety, and pain. U.S. Pat. No. 5,952,381 issuedto Chen et al. discloses certain guanidine compounds for use inselectively inhibiting or antagonizing α_(v)β₃ integrins.

[0009] Various 5-, 6-, and 7-membered fully saturated1-azacarbocyclic-2-ylidene derivatives of guanidine are disclosed ashaving anti-secretory and hypoglycemic activities by U.S. Pat. No.4,211,867 issued to Rasmussen. Such compounds are also taught as usefulfor the treatment of cardiovascular disease. Other guanidine derivativesare disclosed by U.S. Pat. No. 5,885,985 issued to Macdonald et al. asuseful in therapy to treat inflammation.

[0010] Nevertheless, there remains a need for potent and specificagonists of MC4-R that are low molecular weight non-peptide smallmolecules. Methods of treating a melanocortin-4 receptor mediateddisease, such as obesity, with such non-peptide drugs, are alsoparticularly desirable.

SUMMARY OF THE INVENTION

[0011] The instant invention provides potent and specific agonists ofMC4-R that are low molecular weight non-peptide small molecules. Thus,there has been provided, in accordance with one aspect of the invention,a compound of either formula IA or IB:

[0012] wherein

[0013] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0014] R² is selected from the group consisting of substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0015] R³ is selected from the group consisting of substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups;

[0016] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups;

[0017] R⁵ is selected from the group consisting of substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; or

[0018] R⁴ and R⁵, together with the nitrogen to which they are bound,form a substituted or unsubstituted heterocyclyl or heteroaryl group;

[0019] R⁶, R⁷, R⁸, and R⁹ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and

[0020] R¹⁰ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups.

[0021] Compounds provided by the invention further include prodrugs ofthe compounds of either formula IA or IB, pharmaceutically acceptablesalts thereof, stereoisomers thereof, tautomers thereof, hydratesthereof, hydrides thereof, or solvates thereof.

[0022] In one embodiment, R² is selected from the group consisting ofsubstituted and unsubstituted arylalkyl, alkenyl, heteroarylalkyl, andheterocyclylalkyl groups.

[0023] In another embodiment, R³ is selected from the group consistingof substituted and unsubstituted cycloalkyl, alkenyl, alkyl, and arylgroups.

[0024] In another embodiment, R⁴ and R⁵ may be the same or different andare each independently selected from the group consisting of substitutedand unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups.

[0025] In another embodiment, R⁴ and R⁵, together with the nitrogen towhich they are bound, form a substituted or unsubstituted heterocyclylgroup.

[0026] In another embodiment, R⁴ and R⁵, together with the nitrogen towhich they are bound, form a substituted or unsubstituted saturatedheterocyclyl group comprising at least one heteroatom selected from thegroup consisting of O, S, and N in addition to the N atom to which R⁴and R⁵ are bound.

[0027] There has also been provided, in accordance with another aspectof the invention, a compound of either formula IIA or IIB:

[0028] wherein

[0029] at least one of W, X, Y, or Z is a nitrogen atom, forming, e.g.,a pyridyl group;

[0030] R¹ is selected from the group consisting of H, and substitutedand unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0031] R² is selected from the group consisting of substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups;

[0032] R³ is selected from the group consisting of H and substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups;

[0033] R⁴ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups;

[0034] R⁵ is selected from the group consisting of substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; or

[0035] R⁴ and R⁵, together with the nitrogen to which they are bound,form a substituted or unsubstituted heterocyclyl or heteroaryl group;

[0036] R⁶, R⁷, R⁸, and R⁹ may be the same or different, and are eachindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;

[0037] wherein R⁶ may be absent if W is a nitrogen atom;

[0038] wherein R⁷ may be absent if X is a nitrogen atom;

[0039] wherein R⁸ may be absent if Z is a nitrogen atom;

[0040] wherein R⁹ may be absent if Y is a nitrogen atom; and

[0041] R¹⁰ is selected from the group consisting of H, and substitutedand unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, andarylalkyl groups.

[0042] Compounds of either formula IIA or IIB provided by the inventionfurther include prodrugs thereof, pharmaceutically acceptable saltsthereof, stereoisomers thereof, tautomers thereof, hydrates thereof,hydrides thereof, or solvates thereof.

[0043] In another embodiment, R² is selected from the group consistingof substituted and unsubstituted arylalkyl, alkenyl, heteroarylalkyl,and heterocyclylalkyl groups.

[0044] In another embodiment, R³ is selected from the group consistingof substituted and unsubstituted cycloalkyl, alkenyl, alkyl, and arylgroups.

[0045] In another embodiment, R⁴ and R⁵ may be the same or different andare each independently selected from the group consisting of substitutedand unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups.

[0046] In another embodiment, R⁴ and R⁵, together with the nitrogen towhich they are bound, form a substituted or unsubstituted heterocyclylgroup.

[0047] In another embodiment, R⁴ and R⁵, together with the nitrogen towhich they are bound, form a substituted or unsubstituted saturatedheterocyclyl group comprising at least one heteroatom selected from thegroup consisting of O, S, and N in addition to the N atom to which R⁴and R⁵ are bound.

[0048] There has also been provided, in accordance with another aspectof the invention, a composition comprising a compound according to theinstant invention and a pharmaceutically acceptable carrier.

[0049] There has also been provided, in accordance with another aspectof the invention, a method of treating an MC4-R mediated disease,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0050] In one embodiment, a disease to be treated by those methods ofthe instant invention is obesity or type II diabetes.

[0051] Other objects, features and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0052]FIG. 1 is a graph showing the reduction in food intake in obesemice treated intraperitoneally (“IP”) with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0053]FIG. 2 is a graph showing the reduction in body weight in obesemice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0054]FIG. 3 is a graph showing the reduction in fasting glucose levelsin obese mice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0055]FIG. 4 is a graph showing glucose levels during oral glucosetolerance tests in obese mice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamide.

[0056]FIG. 5 is a graph showing the reduction in free fatty acid levelsin obese mice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamide.

[0057]FIG. 6 is a graph showing the acute effect of IP treatment of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon insulin levels.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0058] The instant invention relates to novel classes of small moleculemelanocortin-4 receptor (MC4-R) agonists. These compounds can beformulated into compositions and are useful in activating MC4-R, or inthe treatment of MC4-R-mediated diseases, such as obesity, type IIdiabetes, erectile dysfunction, polycystic ovary disease, complicationsresulting from or associated with obesity and diabetes, and Syndrome X.

[0059] The following definitions are used throughout this specification.

[0060] Alkyl groups include straight chain and branched alkyl groupshaving 1 to about 8 carbon atoms. Examples of straight chain alkylgroups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, andoctyl groups. Examples of branched alkyl groups, include, but notlimited to, isopropyl, sec-butyl, t-butyl, and isopentyl groups.Representative substituted alkyl groups may be substituted one or moretimes with, for example, amino, thio, alkoxy, or halo groups such as F,Cl, Br, and I groups.

[0061] Cycloalkyl groups are cyclic alkyl groups such as, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. Cycloalkyl groups also includesrings that are substituted with straight or branched chain alkyl groupsas defined above, and further include cycloalkyl groups that aresubstituted with other rings including fused rings such as, but notlimited to, decalinyl, tetrahydronaphthyl, and indanyl. Cycloalkylgroups also include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenlyl, isocamphenyl, andcarenyl groups. Representative substituted cycloalkyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl groups ormono-, di- or tri-substituted norbornyl or cycloheptyl groups, which maybe substituted with, for example, alkyl, alkoxy, amino, thio, or halogroups.

[0062] Alkenyl groups are straight chain, branched or cyclic lower alkylgroups having 2 to about 8 carbon atoms, and further including at leastone double bond, as exemplified, for instance, by vinyl, propenyl,2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups amongothers.

[0063] Alkynyl groups are straight chain or branched lower alkyl groupshaving 2 to about 8 carbon atoms, and further including at least onetriple bond, as exemplified by groups, including, but not limited to,ethynyl, propynyl, and butynyl groups.

[0064] Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulene, heptalene, biphenylene, indacene, fluorene, phenanthrene,triphenylene, pyrene, naphthacene, chrysene, biphenyl, anthracenyl, andnaphthenyl groups. Although the phrase “aryl groups” includes groupscontaining fused rings, such as fused aromatic-aliphatic ring systems,it does not include aryl groups that have other groups, such as alkyl orhalo groups, bonded to one of the ring members. Rather, groups such astolyl are referred to as substituted aryl groups. The phrase “arylgroups” includes groups bonded to one or more carbon atom(s), and/ornitrogen atom(s), in the compounds of formulas I and II. Representativesubstituted aryl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or benzyl groups, which may be substituted with groups including,but not limited to, amino, alkoxy, alkyl, or halo.

[0065] Cycloalkylalkyl groups are alkyl groups as defined above in whicha hydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above.

[0066] Arylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to anaryl group as defined above.

[0067] Heterocyclyl groups are nonaromatic ring compounds containing 3or more ring members, of which, one or more is a heteroatom such as, butnot limited to, N, O, and S. The phrase “heterocyclyl group” includesfused ring species including those comprising fused aromatic andnonaromatic groups. The phrase also includes polycyclic ring systemscontaining a heteroatom such as, but not limited to quinuclidyl.However, the phrase does not include heterocyclyl groups that have othergroups, such as alkyl or halo groups, bonded to one of the ring members.Rather, these are referred to as “substituted heterocyclyl groups”.Heterocyclyl groups include, but are not limited to, piperazino,morpholino, thiomorpholino, pyrrolidino, piperidino and homopiperazinogroups. Representative substituted heterocyclyl groups may bemono-substituted or substituted more than once, such as, but not limitedto morpholino or piperazino groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups including, but not limitedto, amino, alkoxy, alkyl, or halo.

[0068] Heteroaryl groups are aromatic ring compounds containing 3 ormore ring members, of which, one or more is a heteroatom such as, butnot limited to, N, O, and S. Heteroaryl groups include, but are notlimited to, groups such as furan, thiophene, pyrrole, isopyrrole,diazole, imidazole, isoimidazole, triazole, dithiole, oxathiole,isoxazole, oxazole, thiazole, isothiazole, oxad iazole, oxatriazole,dioxazole, oxathiazole, pyran, dioxin, pyridine, pyrimidine, pyridazine,pyrazine, triazine, oxazine, isoxazine, oxathiazine, azepin, oxepin,thiepin, diazepine, benzofuran, and isobenzofuran. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heteroaryl groups”.Representative substituted heteroaryl groups may be substituted one ormore times with groups including, but not limited to, amino, alkoxy,alkyl, or halo.

[0069] Heterocyclylalkyl groups are alkyl groups as defined above inwhich a hydrogen or carbon bond of an alkyl group is replaced with abond to a heterocyclyl group as defined above.

[0070] Heteroarylalkyl groups are alkyl groups as defined above in whicha hydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

[0071] Aminocarbonyl groups are groups of the formula RR′NC(O)—, whereinR or R′ may be the same or different, and each is independently selectedfrom H, or substituted or unsubstituted alkyl, cycloalkyl, aryl,heterocyclyl or heteroaryl groups, as defined above.

[0072] In general, “substituted” refers to a group as defined above inwhich one or more bonds to a hydrogen atom contained therein arereplaced by a bond to non-hydrogen or non-carbon atoms such as, but notlimited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, aryloxy groups, and estergroups; a sulfur atom in groups such as thiol groups, alkyl and arylsulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; anitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,amides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups alsoinclude groups in which one or more bonds to a carbon(s) or hydrogen(s)atom is replaced by a bond to a heteroatom such as oxygen in carbonyl,carboxyl, and ester groups; nitrogen in groups such as imines, oximes,hydrazones, and nitrites.

[0073] Substituted cycloalkyl, substituted aryl, substitutedheterocyclyl and substituted heteroaryl also include rings and fusedring systems in which a bond to a hydrogen atom is replaced with a bondto a carbon atom. Therefore, substituted cycloalkyl, substituted aryl,substituted heterocyclyl and substituted heteroaryl groups may besubstituted with alkyl groups as defined above.

[0074] Pharmaceutically acceptable salts include a salt with aninorganic base, organic base, inorganic acid, organic acid, or basic oracidic amino acid. As salts of inorganic bases, the invention includes,for example, alkali metals such as sodium or potassium, alkali earthmetals such as calcium and magnesium or aluminum, and ammonia. As saltsof organic bases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

[0075] Prodrugs, as used in the context of the instant invention,includes those derivatives of the instant compounds which undergo invivo metabolic biotransformation, by enzymatic or nonenzymaticprocesses, such as hydrolysis, to form a compound of the invention.Prodrugs can be employed to improve pharmaceutical or biologicalproperties, as for example solubility, melting point, stability andrelated physicochemical properties, absorption, pharmacodynamics andother delivery-related properties.

[0076] The instant invention provides potent and specific agonists ofMC4-R that are low molecular weight, non-peptide small molecules. Inaccordance with one aspect of the invention, the invention provides afirst group of compounds of either formula IA or IB such as shown below.

[0077] Compounds of the invention further include prodrugs of the firstgroup of compounds of either formula IA or IB, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof,hydrates thereof, hydrides thereof, or solvates thereof.

[0078] In the first group of compounds of formula IA and IB, R¹ isselected from H, substituted or unsubstituted arylalkyl groups,substituted or unsubstituted heteroarylalkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heteroarylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted cycloalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted cycloalkylalkylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, or substituted or unsubstituted alkylgroups. In various embodiments, R¹ is H.

[0079] In the first group of compounds of formula IA and IB, R² isselected from substituted or unsubstituted arylalkyl groups, substitutedor unsubstituted heteroarylalkyl groups, substituted or unsubstitutedaryl groups, substituted or unsubstituted heteroaryl groups, substitutedor unsubstituted heterocyclyl groups, substituted or unsubstitutedcycloalkyl groups, substituted or unsubstituted heterocyclylalkylgroups, substituted or unsubstituted cycloalkylalkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, or substituted or unsubstituted alkyl groups. In variousembodiments, R² is selected from substituted or unsubstituted arylalkylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted heteroarylalkyl groups, or substituted or unsubstitutedheterocyclylalkyl groups. In still other embodiments, R² is a2,4-disubstituted phenethyl groups such as, but not limited to a2,4-dihalophenethyl group or a 2,4-dialkylphenethyl group. In stillother embodiment, R² is selected from phenethyl, 2,4-dichlorophenethyl,4-methoxyphenethyl, 4-bromophenethyl, 4-methylphenethyl,4-chlorophenethyl, 4-chlorobenzyl, 4-ethylphenethyl, cyclohexenylethyl,2-methoxyphenethyl, 2-chlorophenethyl, 2-fluorophenethyl,3-methoxyphenethyl, 3-fluorophenethyl, thienylethyl, indolylethyl,4-hydroxyphenethyl, 3,4-dimethoxyphenethyl, 2-chloro-4-iodophenethyl,2-fluoro-4-methylphenethyl, 2-fluoro-4-bromophenethyl,2-fluoro-4-methoxyphenethyl, 2-trifluoromethyl-4-fluorophenethyl,2,4-difluorophenethyl, 2,4-dimethylphenethyl, or 2,4-dimethoxyphenethylgroups.

[0080] In the first group of compounds of formula IA and IB, R³ isselected from substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted heteroaryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, substituted or unsubstituted arylalkyl groups, substituted orunsubstituted heteroarylalkyl groups, or substituted or unsubstitutedcycloalkylalkyl groups. In various embodiments, R³ is selected fromsubstituted or unsubstituted cycloalkyl groups, substituted orunsubstituted polycyclic cycloalkyl groups, substituted or unsubstitutedalkenyl groups, substituted or unsubstituted alkyl groups, orsubstituted or unsubstituted aryl groups. In another embodiment, R³ isselected from substituted or unsubstituted cyclohexyl groups,substituted or unsubstituted 2-alkylcyclohexyl groups, substituted orunsubstituted 2,2-dialkylcyclohexyl groups, substituted or unsubstituted2,3-dialkylcyclohexyl groups, substituted or unsubstituted2,4-dialkylcyclohexyl groups, substituted or unsubstituted2,5-dialkylcyclohexyl groups, substituted or unsubstituted2,6-dialkylcyclohexyl groups, substituted or unsubstituted3,4-dialkylcyclohexyl groups, substituted or unsubstituted3-alkylcyclohexyl groups, substituted or unsubstituted 4-alkylcyclohexylgroups, substituted or unsubstituted 3,3,5-trialkylcyclohexyl groups,substituted or unsubstituted cyclohexylmethyl groups, substituted orunsubstituted 2-aminocyclohexyl groups, substituted or unsubstituted3-aminocyclohexyl groups, substituted or unsubstituted 4-aminocyclohexylgroups, substituted or unsubstituted 2,3-diaminocyclohexyl groups,substituted or unsubstituted 2,4-diaminocyclohexyl groups, substitutedor unsubstituted 3,4-diaminocyclohexyl groups, substituted orunsubstituted 2,5-diaminocyclohexyl groups, substituted or unsubstituted2,6-diaminocyclohexyl groups, substituted or unsubstituted2,2-diaminocyclohexyl groups, substituted or unsubstituted2-alkoxycyclohexyl groups, substituted or unsubstituted3-alkoxycyclohexyl groups, substituted or unsubstituted4-alkoxycyclohexyl groups, substituted or unsubstituted2,3-dialkoxycyclohexyl groups, substituted or unsubstituted2,4-dialkoxycyclohexyl groups, substituted or unsubstituted3,4-dialkoxycyclohexyl groups, substituted or unsubstituted2,5-dialkoxycyclohexyl groups, substituted or unsubstituted2,6-dialkoxycyclohexyl groups, substituted or unsubstituted2,2-dialkoxycyclohexyl groups, substituted or unsubstituted2-alkylthiocyclohexyl groups, substituted or unsubstituted3-alkylthiocyclohexyl groups, 4-alkylthiocyclohexyl groups, substitutedor unsubstituted 2,3-dialkylthiocyclohexyl groups, substituted orunsubstituted 2,4-dialkylthiocyclohexyl groups, substituted orunsubstituted 3,4-dialkylthiocyclohexyl groups, substituted orunsubstituted 2,5-dialkylthiocyclohexyl groups, substituted orunsubstituted 2,6-dialkylthiocyclohexyl groups, substituted orunsubstituted 2,2-dialkylthiocyclohexyl groups, substituted orunsubstituted cyclopentyl groups, substituted or unsubstitutedcycloheptyl groups, substituted or unsubstituted cyclohexenyl groups,substituted or unsubstituted isopropyl groups, substituted orunsubstituted n-butyl groups, substituted or unsubstituted cyclooctylgroups, substituted or unsubstituted 2-arylcyclohexyl groups,substituted or unsubstituted 2-phenylcyclohexyl groups, substituted orunsubstituted 2-arylalkylcyclohexyl groups, substituted or unsubstituted2-benzylcyclohexyl groups, substituted or unsubstituted4-phenylcyclohexyl groups, substituted or unsubstituted adamantylgroups, substituted or unsubstituted isocamphenyl groups, substituted orunsubstituted carenyl groups, substituted or unsubstituted7,7-dialkylnorbornyl groups, substituted or unsubstituted bornyl groups,substituted or unsubstituted norbornyl groups, or substituted orunsubstituted decalinyl groups. In another embodiment, R³ is selectedfrom substituted or unsubstituted cyclohexyl groups, substituted orunsubstituted 2-methylcyclohexyl groups, substituted or unsubstituted2,2-dimethylcyclohexyl groups, substituted or unsubstituted2,3-dimethylcyclohexyl groups, substituted or unsubstituted2,4-dimethylcyclohexyl groups, substituted or unsubstituted2,5-dimethylcyclohexyl groups, substituted or unsubstituted2,6-dimethylcyclohexyl groups, substituted or unsubstituted3,4-dimethylcyclohexyl groups, substituted or unsubstituted3-methylcyclohexyl groups, substituted or unsubstituted4-methylcyclohexyl groups, substituted or unsubstituted cyclohex-3-enylgroups, substituted or unsubstituted 3,3,5-trimethylcyclohexyl groups,substituted or unsubstituted 4-t-butylcyclohexyl groups, substituted orunsubstituted 2-methylcycloheptyl groups, substituted or unsubstitutedcyclohexylmethyl groups, substituted or unsubstituted isopinocampheylgroups, substituted or unsubstituted 7,7-dimethylnorbornyl groups,substituted or unsubstituted 4-isopropylcyclohexyl groups, or3-methylcycloheptyl groups.

[0081] In the first group of compounds of formula IA and IB, R⁴ isselected from hydrogen, substituted or unsubstituted alkyl groups,substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted cycloalkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heteroaryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted arylalkyl groups,substituted or unsubstituted heteroarylalkyl groups, or substituted orunsubstituted cycloalkylalkyl groups.

[0082] In the first group of compounds of formula IA and IB, R⁵ isselected from substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heteroarylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted arylalkyl groups, substituted or unsubstitutedheteroarylalkyl groups, or substituted or unsubstituted cycloalkylalkylgroups.

[0083] In alternative embodiments of the first group of compounds offormula IA and IB, R⁴ and R⁵, together with the nitrogen to which theyare bound, form a substituted or unsubstituted heterocyclyl orheteroaryl group. In another such embodiment, R⁴ and R⁵, together withthe nitrogen to which they are bound, form a substituted orunsubstituted saturated heterocyclyl group comprising at least oneheteroatom selected from O, S, or N in addition to the N atom to whichR⁴ and R⁵ are bound. In another embodiment, R⁴ and R⁵, together with thenitrogen to which they are bound, form a substituted or unsubstitutedheterocyclyl ring containing at least one additional nitrogenheteroatom. In still another embodiment, R⁴ and R⁵, together with thenitrogen to which they are bound, form a substituted or unsubstitutedheterocyclyl ring containing at least one additional oxygen heteroatom.Representative examples of the above-described heterocyclyl embodimentsinclude those for which R⁴ and R⁵ together with the nitrogen atom towhich they are attached form a substituted or unsubstituted piperazino,morpholino, pyrrolidino, piperidino, homopiperazino, or azepino group.In another, more specific, embodiment, R⁴ and R⁵, together with thenitrogen to which they are bound, form a substituted piperazino; and, instill more specific embodiments, R⁴ and R⁵, together with the nitrogento which they are bound, form a substituted piperazino group optionallysubstituted by one or two alkyl groups, for example, one or two methylgroups.

[0084] In another embodiment of the first group of compounds of formulaIA and IB, R⁴ is H and R⁵ is selected from substituted or unsubstitutedalkyl groups, substituted or unsubstituted arylalkyl groups, orsubstituted or unsubstituted heteroarylalkyl groups. In anotherembodiment, R⁴ is H and R⁵ is selected from substituted or unsubstituteddialkylaminoethyl groups, substituted or unsubstituted 4-ethylbenzylgroups, substituted or unsubstituted 3-chlorobenzyl groups, substitutedor unsubstituted 2,4-dichlorobenzyl groups, substituted or unsubstituted3-methylbenzyl groups, substituted or unsubstituted benzyl groups,substituted or unsubstituted 4-fluorobenzyl groups, substituted orunsubstituted 3-methoxybenzyl groups, substituted or unsubstituted2-chlorobenzyl groups, or substituted or unsubstituted thiophene groups.In another embodiment, R⁴ and R⁵ may be the same or different and areeach independently selected from substituted or unsubstituted alkylgroups, substituted or unsubstituted arylalkyl groups, or substituted orunsubstituted heteroarylalkyl groups. In another embodiment, R⁴ and R⁵may be the same or different and are each independently selected fromsubstituted or unsubstituted dialkylaminoethyl groups, substituted orunsubstituted 4-ethylbenzyl groups, substituted or unsubstituted3-chlorobenzyl groups, substituted or unsubstituted 2,4-dichlorobenzylgroups, substituted or unsubstituted 3-methylbenzyl groups, substitutedor unsubstituted benzyl groups, substituted or unsubstituted4-fluorobenzyl groups, substituted or unsubstituted 3-methoxybenzylgroups, substituted or unsubstituted 2-chlorobenzyl groups, andsubstituted or unsubstituted thiophene groups.

[0085] In the first group of compounds of formula IA and IB, R⁶, R⁷, R⁸,and R⁹ may be the same or different, and are each independently selectedfrom H, Cl, I, F, Br, OH, NH₂, CN, NO₂, substituted or unsubstitutedalkoxy groups, substituted or unsubstituted amino groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, substituted orunsubstituted alkylamino groups, substituted or unsubstituteddialkylamino groups, substituted or unsubstituted cycloalkyl groups,substituted or unsubstituted heterocyclylamino groups, substituted orunsubstituted heteroarylamino groups, substituted or unsubstitutedaminocarbonyl groups, substituted or unsubstituted alkylaminocarbonylgroups, substituted or unsubstituted dialkylaminocarbonyl groups,substituted or unsubstituted cycloalkylaminocarbonyl groups, substitutedor unsubstituted arylaminocarbonyl groups, substituted or unsubstitutedheterocyclylaminocarbonyl groups, or substituted or unsubstitutedheteroarylaminocarbonyl groups.

[0086] In the first group of compounds of formula IA and IB, R¹⁰ isselected from H, substituted or unsubstituted alkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkylalkyl groups, substitutedor unsubstituted aryl groups, or substituted or unsubstituted arylalkylgroups. In various embodiments, R¹⁰ is H.

[0087] There has also been provided, in accordance with another aspectof the invention, a second group of compound of either formula IA or IB:

[0088] Compounds of the invention further include prodrugs of the secondgroup of compounds of either formula IA or IB, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof,hydrates thereof, hydrides thereof, or solvates thereof.

[0089] In the second group of compound of formula IA and IB, R¹ isselected from H, substituted or unsubstituted arylalkyl groups,substituted or unsubstituted heteroarylalkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedcycloalkylalkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, or substituted orunsubstituted alkyl groups. In various embodiments, R¹ is H.

[0090] In the second group of compound of formula IA and IB, R² isselected from substituted or unsubstituted arylalkyl groups, substitutedor unsubstituted heteroarylalkyl groups, substituted or unsubstitutedaryl groups, substituted or unsubstituted heterocyclyl groups,substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedcycloalkylalkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, or substituted orunsubstituted alkyl groups. In another embodiment, R² is selected fromsubstituted or unsubstituted arylalkyl, alkenyl, heteroarylalkyl, orheterocyclylalkyl groups. In another embodiment, R² is 2,4-disubstitutedphenethyl. In still another embodiment, R² is selected from2,4-dihalophenethyl, or 2,4-dialkylphenethyl. In another embodiment, R²is selected from phenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl,4-bromophenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl,4-ethylphenethyl, cyclohexenylethyl, 2-methoxyphenethyl,2-chlorophenethyl, 2-fluorophenethyl, 3-methoxyphenethyl,3-fluorophenethyl, thienylethyl, indolylethyl, 4-hydroxyphenethyl,3,4-dimethoxyphenethyl, 2-chloro-4-iodophenethyl,2-fluoro-4-methylphenethyl, 2-fluoro-4-bromophenethyl,2-fluoro-4-methoxyphenethyl, 2-trifluoromethyl-4-fluorophenethyl,2,4-difluorophenethyl, 2,4-dimethylphenethyl, or 2,4-dimethoxyphenethylgroups.

[0091] In the second group of compound of formula IA and IB, R³ isselected from H, substituted or unsubstituted alkyl groups, substitutedor unsubstituted alkenyl, alkynyl groups, substituted or unsubstitutedcycloalkyl groups, substituted or unsubstituted aryl groups, substitutedor unsubstituted heteroaryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted arylalkyl groups,substituted or unsubstituted heteroarylalkyl groups, or substituted orunsubstituted cycloalkylalkyl groups. In various embodiments, R³ isselected from substituted or unsubstituted cycloalkyl groups,substituted or unsubstituted polycyclic cycloalkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted alkylgroups, or substituted or unsubstituted aryl groups. In variousembodiments, R³ is selected from substituted or unsubstitutedcyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, or decalinyl groups.In another embodiment, R³ is selected from substituted or unsubstitutedcyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl,2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl,2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, 2-methylcycloheptyl, cyclohexylmethyl,isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, or3-methylcycloheptyl groups.

[0092] In the second group of compound of formula IA and IB, R⁴ and R⁵,together with the N atom to which they are bound, form a substituted orunsubstituted saturated heterocyclyl group comprising at least oneheteroatom selected from the group consisting of O, S, and N in additionto the N atom to which R⁴ and R⁵ are bound. In another embodiment, R⁴and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl ring containing at least oneadditional nitrogen heteroatom. In still another embodiment, R⁴ and R⁵,together with the nitrogen to which they are bound, form a substitutedor unsubstituted heterocyclyl ring containing at least one additionaloxygen heteroatom. Representative examples of the above-describedheterocyclyl embodiments include those for which R⁴ and R⁵ together withthe nitrogen atom to which they are attached form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group. In another, more specific, embodiment,R⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted piperazino; and, in still more specific embodiments, R⁴ andR⁵, together with the nitrogen to which they are bound, form asubstituted piperazino group optionally substituted by one or two alkylgroups, for example, one or two methyl groups.

[0093] In the second group of compound of formula IA and IB, R⁶, R⁷, R⁸,and R⁹ may be the same or different, and are each independently selectedfrom H, Cl, I, F, Br, OH, NH₂, CN, NO₂, substituted or unsubstitutedalkoxy groups, substituted or unsubstituted amino groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, substituted orunsubstituted alkylamino groups, substituted or unsubstituteddialkylamino groups, substituted or unsubstituted cycloalkyl groups,substituted or unsubstituted heterocyclylamino groups, substituted orunsubstituted heteroarylamino groups, substituted or unsubstitutedaminocarbonyl groups, substituted or unsubstituted alkylaminocarbonylgroups, substituted or unsubstituted dialkylaminocarbonyl groups,substituted or unsubstituted cycloalkylaminocarbonyl groups, substitutedor unsubstituted arylaminocarbonyl groups, substituted or unsubstitutedheterocyclylaminocarbonyl groups, or substituted or unsubstitutedheteroarylaminocarbonyl groups.

[0094] In the second group of compound of formula IA and IB, R¹⁰ isselected from H, substituted or unsubstituted arylalkyl groups,substituted or unsubstituted heteroarylalkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heteroarylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted cycloalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted cycloalkylalkylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, or substituted or unsubstituted alkylgroups. In one embodiment R¹⁰ is H.

[0095] There has also been provided, in accordance with another aspectof the invention, a compound of either formula IIA or IIB:

[0096] Compounds of the invention further include prodrugs of thecompounds of either formula IIA or IIB, pharmaceutically acceptablesalts thereof, stereoisomers thereof, tautomers thereof, hydratesthereof, hydrides thereof, or solvates thereof.

[0097] In the compounds of formula IIA and IIB, W, X, Y, and Z arecarbon or nitrogen. In some embodiments, at least one of W, X, Y, or Zis a nitrogen atom. In more specific embodiments, three of W, X, Y, andZ are carbon, and one of W, X, Y, and Z is nitrogen, forming, thereby apyridyl group. In more particular embodiments, each of X, Y, and Z iscarbon, and W is nitrogen. Still other more particular embodiments arethose for which each of W, X, and Z is carbon, and Y is nitrogen.

[0098] In the compounds of formula IIA and IIB, R¹ is selected from H,substituted or unsubstituted arylalkyl groups, substituted orunsubstituted heteroarylalkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted heteroaryl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedcycloalkyl groups, substituted or unsubstituted heterocyclylalkylgroups, substituted or unsubstituted cycloalkylalkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, or substituted or unsubstituted alkyl groups. In variousembodiments, R¹ is H.

[0099] In the compounds of formula IIA and IIB, R² is selected fromsubstituted or unsubstituted arylalkyl groups, substituted orunsubstituted heteroarylalkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted heteroaryl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedcycloalkyl groups, substituted or unsubstituted heterocyclylalkylgroups, substituted or unsubstituted cycloalkylalkyl groups, substitutedor unsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, or substituted or unsubstituted alkyl groups. In variousembodiments, R² is selected from substituted or unsubstituted arylalkyl,alkenyl, heteroarylalkyl, or heterocyclylalkyl groups. In otherembodiments, R² is 2,4-disubstituted phenethyl. In another embodiment,R² is selected from 2,4-dihalophenethyl or 2,4-dialkylphenethyl groups.In another embodiment, R² is selected from substituted or unsubstitutedphenethyl, 2,4-dichlorophenethyl, 4-methoxyphenethyl, 4-bromophenethyl,4-methylphenethyl, 4-chlorophenethyl, 4-chlorobenzyl, 4-ethylphenethyl,cyclohexenylethyl, 2-methoxyphenethyl, 2-chlorophenethyl,2-fluorophenethyl, 3-methoxyphenethyl, 3-fluorophenethyl, thienylethyl,indolylethyl, 4-hydroxyphenethyl, 3,4-dimethoxyphenethyl,2-chloro-4-iodophenethyl, 2-fluoro-4-methylphenethyl,2-fluoro-4-bromophenethyl, 2-fluoro-4-methoxyphenethyl,2-trifluoromethyl-4-fluorophenethyl, 2,4-difluorophenethyl,2,4-dimethylphenethyl, or 2,4-dimethoxyphenethyl groups.

[0100] In the compounds of formula IIA and IIB, R³ is selected from H,substituted or unsubstituted alkyl groups, substituted or unsubstitutedalkenyl groups, substituted or unsubstituted alkynyl groups, substitutedor unsubstituted cycloalkyl groups, substituted or unsubstitutedheteroaryl groups, substituted or unsubstituted heterocyclyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted arylalkyl groups, substituted or unsubstitutedheteroarylalkyl groups, or substituted or unsubstituted cycloalkylalkylgroups. In various embodiments, R³ is selected from substituted orunsubstituted cycloalkyl, polycyclic cycloalkyl, alkenyl, alkyl, or arylgroups. In other embodiments, R³ is selected from substituted orunsubstituted cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, norbornyl, bornyl, or decalinyl groups.In other embodiment, R³ is selected from substituted or unsubstitutedcyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl,2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl,2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, cyclohexyl methyl, isopinocampheyl,7,7-dimethyinorbornyl, 4-isopropylcyclohexyl, or 3-methylcycloheptylgroups.

[0101] In the compounds of formula IIA and IIB, R⁴ is selected from theH, substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heteroarylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted arylalkyl groups, substituted or unsubstitutedheteroarylalkyl groups, or substituted or unsubstituted cycloalkylalkylgroups.

[0102] In the compounds of formula IIA and IIB, R⁵ is selected fromsubstituted or unsubstituted alkyl groups, substituted or unsubstitutedalkenyl groups, substituted or unsubstituted alkynyl groups, substitutedor unsubstituted cycloalkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted heteroaryl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedarylalkyl groups, substituted or unsubstituted heteroarylalkyl groups,or substituted or unsubstituted cycloalkylalkyl groups.

[0103] In some embodiments of compounds of formula IIA and IIB, R⁴ is Hand R⁵ is selected from substituted or unsubstituted alkyl, arylalkyl,and heteroarylalkyl groups. In other embodiments, R⁴ is H and R⁵ isselected from substituted or unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups. In other embodiments, R⁴ and R⁵ may be the same or different andare each independently selected from substituted or unsubstituted alkyl,arylalkyl, or heteroarylalkyl groups. In various other embodiments, R⁴and R⁵ may be the same or different and are each independently selectedfrom substituted or unsubstituted dialkylaminoethyl, 4-ethylbenzyl,3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl, benzyl,4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, or thiophene groups.

[0104] In the compounds of formula IIA and IIB, R⁴ and R⁵, together withthe nitrogen to which they are bound, may form a substituted orunsubstituted heterocyclyl or heteroaryl group. In another suchembodiment, R⁴ and R⁵, together with the nitrogen to which they arebound, form a substituted or unsubstituted saturated heterocyclyl groupcomprising at least one heteroatom selected from O, S, or N in additionto the N atom to which R⁴ and R⁵ are bound. In another embodiment, R⁴and R⁵, together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl ring containing at least oneadditional nitrogen heteroatom. In still another embodiment, R⁴ and R⁵,together with the nitrogen to which they are bound, form a substitutedor unsubstituted heterocyclyl ring containing at least one additionaloxygen heteroatom. Representative examples of the above-describedheterocyclyl embodiments include those for which R⁴ and R⁵ together withthe nitrogen atom to which they are attached form a substituted orunsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group. In another, more specific, embodiment,R⁴ and R⁵, together with the nitrogen to which they are bound, form asubstituted piperazino; and, in still more specific embodiments, R⁴ andR⁵, together with the nitrogen to which they are bound, form asubstituted piperazino group optionally substituted by one or two alkylgroups, for example, one or two methyl groups.

[0105] In the compounds of formula IIA and IIB, R⁶, R⁷, R⁸, and R⁹ maybe the same or different, and are each independently selected from H,Cl, I, F, Br, OH, NH₂, CN, NO₂, substituted or unsubstituted alkoxygroups, substituted or unsubstituted amino groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted alkenyl groups,substituted or unsubstituted alkynyl groups, substituted orunsubstituted alkylamino groups, substituted or unsubstituteddialkylamino groups, substituted or unsubstituted cycloalkyl groups,substituted or unsubstituted heterocyclylamino groups, substituted orunsubstituted heteroarylamino groups, substituted or unsubstitutedaminocarbonyl groups, substituted or unsubstituted alkylaminocarbonylgroups, substituted or unsubstituted dialkylaminocarbonyl groups,substituted or unsubstituted cycloalkylaminocarbonyl groups, substitutedor unsubstituted arylaminocarbonyl groups, substituted or unsubstitutedheterocyclylaminocarbonyl groups, or substituted or unsubstitutedheteroarylaminocarbonyl groups. In compounds of formula IIA and IIB, R⁶may be absent if W is a nitrogen atom; R⁷ may be absent if X is anitrogen atom; R⁸ may be absent if Z is a nitrogen atom; and R⁹ may beabsent if Y is a nitrogen atom.

[0106] In the compounds of formula IIA and IIB, R¹⁰ is selected from H,and substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted cycloalkylalkyl groups, substitutedor unsubstituted aryl groups, or arylalkyl groups. In some embodiments,R¹⁰ is H.

[0107] There has also been provided, in accordance with another aspectof the invention, a composition comprising a compound according to theinstant invention and a pharmaceutically acceptable carrier.

[0108] There has also been provided, in accordance with another aspectof the invention, a method of activating MC4-R in a subject, comprisingadministering to a subject in need thereof an effective amount of acompound or composition of the instant invention.

[0109] There has also been provided, in accordance with another aspectof the invention, a method of treating an MC4-R-mediated disease,comprising administering to a subject in need thereof, a compound orcomposition of the instant invention.

[0110] In one embodiment, a disease to be treated by those methods ofthe instant invention is obesity, or type I or type II diabetes.

[0111] In another embodiment, a condition to be treated by those methodsof the instant invention is a condition associated with or acomplication arising from obesity or type II diabetes.

[0112] In another embodiment, a condition to be treated by those methodsof the instant invention is erectile dysfunction.

[0113] In another embodiment, a disease to be treated by those methodsof the instant invention is polycystic ovary disease.

[0114] In another embodiment, a disease to be treated by those methodsof the instant invention is Syndrome X.

[0115] The invention also includes tautomers of the instant compounds.For example, the instant invention also includes those tautomers offormula IA such as the following where R¹⁰ is H in formula IA above andthe following structure shows the tautomer:

[0116] Similarly, the instant invention also contemplates thosetautomers of compounds of formula IIA, such as the following where R¹⁰is H in formula IIA above and the following structure shows thestructure of the tautomer:

[0117] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ W, X, Y and Z areas defined herein. The instant invention also, therefore, includesprodrugs, pharmaceutically acceptable salts, stereoisomers, hydrates,hydrides, or solvates of these tautomers.

[0118] The instant compounds may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. In some cases, one stereoisomer may be moreactive and/or may exhibit beneficial effects in comparison to otherstereoisomer(s) or when separated from the other stereoisomer(s).However, it is well within the skill of the ordinary artisan toseparate, and/or to selectively prepare said stereoisomers. Accordingly,“stereoisomers” of the instant invention necessarily includes mixturesof stereoisomers, individual stereoisomers, or optically active forms.

[0119] Generally, compounds of formula IA may be prepared, for example,by a method comprising coupling of a compound of formula R¹R²NH with4-azidobenzoic acid to give W:

[0120] Compound W is then reacted with a leaving group, such as, forexample, triphenylphosphine (PPh₃), to give X:

[0121] The intermediate of formula X is then contacted with anisocyanate of formula OCNR³ and a compound of formula R⁴R⁵HN to obtain acompound of formula IA above, prodrugs thereof, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof,hydrates thereof, hydrides thereof, or solvates thereof, wherein R¹, R²,R³, R⁴, R⁵, and R⁶ are as defined above. It will also be appreciatedthat other groups may replace PPh₃, such as, for example, any phosphines(PR₃), phosphites {P(OR)₃}, or arsine (AsPh₃).

[0122] Preparation of compounds of formula IA wherein R¹⁰ is hydrogencan be summarized, for example, by the following synthesis scheme:

[0123] Compound of formula IA in which R¹⁰ is a substituent other thanhydrogen (e.g. alkyl or aralkyl) can be prepared as follows.

[0124] Compounds having the general structure shown in formula IB can beprepared using the generic synthetic scheme shown below.

[0125] Alternatively, compounds of formula IIA may be prepared, forexample, by a method comprising contacting a compound of formula R¹R²HNwith a compound of formula Y:

[0126] to obtain an intermediate of formula Z:

[0127] The intermediate of formula Z is then contacted with anisocyanate of formula OCNR³ and a compound of formula R⁴R⁵HN to obtain acompound of formula IIA above, prodrugs thereof, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof,hydrates thereof, hydrides thereof, or solvates thereof, wherein R¹, R²,R³, R⁴, R⁵, and R⁶ are as defined above.

[0128] Specifically, compounds of the instant invention may be prepared,for example, by reacting a suitable azidobenzoic acid, or a suitableacid halide thereof, with a suitable amino compound represented offormula R¹R²HN. The reaction may be carried out in solid phase in thepresence of an inert solvent, for example, an aprotic solvent such aspyridine, methylene chloride, tetrahydrofuran, N,N-dimethylformamide ordimethylsulfoxide, or a mixture thereof. The condensation product may beoptionally purified, and is reacted with phosphine, a suitableisocyanate of formula OCNR³ and a compound of formula R⁴R⁵HN. Theaddition product may then be deprotected from the resin, if needed, byelution with a suitable acid such as a 4:1 mixture of trifluoroaceticacid and methylene chloride. Further purification can be accomplishedthrough conventional means such as filtration, extraction andre-crystallization.

[0129] The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like, to treat or ameliorate a variety of disorders. Examples ofsuch disorders include, but are not limited to obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,inflammation, fever, cognitive disorders, sexual behavior disorders. Atherapeutically effective dose further refers to that amount of one ormore compounds of the instant invention sufficient to result inamelioration of symptoms of the disorder. The pharmaceuticalcompositions of the instant invention can be manufactured by methodswell known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, emulsifying or levigatingprocesses, among others. The compositions can be in the form of, forexample, granules, powders, tablets, capsules, syrup, suppositories,injections, emulsions, elixirs, suspensions or solutions. The instantcompositions can be formulated for various routes of administration, forexample, by oral administration, by intranasal administration, bytransmucosal administration, by rectal administration, or subcutaneousadministration as well as intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.The compound or compounds of the instant invention can also beadministered in a local rather than a systemic fashion, such asinjection as a sustained release formulation. The following dosage formsare given by way of example and should not be construed as limiting theinstant invention.

[0130] For oral, buccal, and sublingual administration, powders,suspensions, granules, tablets, pills, capsules, gelcaps, and capletsare acceptable as solid dosage forms. These can be prepared, forexample, by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, with at leastone additive or excipient such as a starch or other additive. Suitableadditives or excipients are sucrose, lactose, cellulose sugar, mannitol,maltitol, dextran, sorbitol, starch, agar, alginates, chitins,chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens,casein, albumin, synthetic or semi-synthetic polymers or glycerides,methyl cellulose, hydroxypropylmethyl-cellulose, and/orpolyvinylpyrrolidone. Optionally, oral dosage forms can contain otheringredients to aid in administration, such as an inactive diluent, orlubricants such as magnesium stearate, or preservatives such as parabenor sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol orcysteine, a disintegrating agent, binders, a thickeners, buffers, asweeteners, flavoring agents or perfuming agents. Additionally,dyestuffs or pigments may be added for identification. Tablets and pillsmay be further treated with suitable coating materials known in the art.

[0131] Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, may beadded for oral or parenteral administration.

[0132] As noted above, suspensions may include oils. Such oils include,but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oiland olive oil. Suspension preparation may also contain esters of fattyacids such as ethyl oleate, isopropyl myristate, fatty acid glyceridesand acetylated fatty acid glycerides. Suspension formulations mayinclude alcohols, such as, but not limited to, ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas but not limited to, poly(ethyleneglycol), petroleum hydrocarbons suchas mineral oil and petrolatum; and water may also be used in suspensionformulations.

[0133] For intranasal administration (e.g., to deliver compounds to thebrain), or administration by inhalation (e.g., to deliver compoundsthrough the lungs), the pharmaceutical formulations may be a solution, aspray, a dry powder, or aerosol containing any appropriate solvents andoptionally other compounds such as, but not limited to, stabilizers,antimicrobial agents, antioxidants, pH modifiers, surfactants,bioavailability modifiers and combinations of these. Examples ofintranasal formulations and methods of administration can be found in WO01/41782, WO 00133813, WO 91/97947, U.S. Pat. Nos. 6,180,603, and5,624,898. A propellant for an aerosol formulation may includecompressed air, nitrogen, carbon dioxide, or a hydrocarbon based lowboiling solvent. The compound or compounds of the instant invention areconveniently delivered in the form of an aerosol spray presentation froma nebulizer or the like.

[0134] Injectable dosage forms generally include aqueous suspensions oroil suspensions which may be prepared using a suitable dispersant orwetting agent and a suspending agent. Injectable forms may be insolution phase or in the form of a suspension, which is prepared with asolvent or diluent. Acceptable solvents or vehicles include sterilizedwater, Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0135] For injection, the pharmaceutical formulation may be a powdersuitable for reconstitution with an appropriate solution as describedabove. Examples of these include, but are not limited to, freeze dried,rotary dried or spray dried powders, amorphous powders, granules,precipitates, or particulates. For injection, the formulations mayoptionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these. The compounds maybe formulated for parenteral administration by injection such as bybolus injection or continuous infusion. A unit dosage form for injectionmay be in ampoules or in multi-dose containers.

[0136] For rectal administration, the pharmaceutical formulations may bein the form of a suppository, an ointment, an enema, a tablet or a creamfor release of compound in the intestines, sigmoid flexure and/orrectum. Rectal suppositories are prepared by mixing one or morecompounds of the instant invention, or pharmaceutically acceptable saltsor tautomers of the compound, with acceptable vehicles, for example,cocoa butter or polyethylene glycol, which is present in a solid phaseat normal storing temperatures, and present in a liquid phase at thosetemperatures suitable to release a drug inside the body, such as in therectum. Oils may also be employed in the preparation of formulations ofthe soft gelatin type and suppositories. Water, saline, aqueous dextroseand related sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

[0137] Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

[0138] The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

[0139] The instant compositions may also comprise, for example, micellesor liposomes, or some other encapsulated form, or may be administered inan extended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

[0140] A therapeutically effective dose refers to that amount of thecompound that results in amelioration of symptoms. Specific dosages maybe adjusted depending on conditions of disease, the age, body weight,general health conditions, sex, diet of the subject, dose intervals,administration routes, excretion rate, and combinations of drugs. Any ofthe above dosage forms containing effective amounts are well within thebounds of routine experimentation and therefore, well within the scopeof the instant invention. A therapeutically effective dose may varydepending upon the route of administration and dosage form. Thepreferred compound or compounds of the instant invention is aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

[0141] The present invention also provides methods of enhancing MC4-Ractivity in a human or non-human animal. The method comprisesadministering an effective amount of a compound, or composition, of theinstant invention to said mammal or non-human animal. Effective amountsof the compounds of the instant invention include those amounts thatactivate MC4-R which are detectable, for example, by an assay describedbelow in the illustrative Examples, or any other assay known by thoseskilled in the art that a detect signal transduction, in a biochemicalpathway, through activation of G-protein coupled receptors, for example,by measuring an elevated cAMP level as compared to a control model.Accordingly, “activating” means the ability of a compound to initiate adetectable signal. Effective amounts may also include those amountswhich alleviate symptoms of a MC4-R disorder treatable by activatingMC4-R.

[0142] An MC4-R disorder, or MC4-R-mediated disease, which may betreated by those methods provided, include any biological disorder ordisease in which MC4-R is implicated, or which inhibition of MC4-Rpotentiates a biochemical pathway that is defective in the disorder ordisease state. Examples of such diseases are obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,inflammation, fever, cognitive disorders, type II diabetes, polycysticovary disease, Syndrome X, complications from obesity and diabetes, andsexual behavior disorders. In a preferred embodiment, the instantinvention provides compounds, compositions, and methods effective forreducing energy intake and body weight; reducing serum insulin andglucose levels; alleviating insulin resistance; and reducing serumlevels of free fatty acids. Accordingly, the instant invention isparticularly effective in treating those disorders or diseasesassociated with obesity or type II diabetes.

[0143] “Treating” within the context of the instant invention,therefore, means an alleviation of symptoms associated with a disorderor disease, or halt of further progression or worsening of thosesymptoms, or prevention or prophylaxis of the disease or disorder. Forexample, within the context of obesity, successful treatment may includean alleviation of symptoms or halting the progression of the disease, asmeasured by reduction in body weight, or a reduction in amount of foodor energy intake. In this same vein, successful treatment of type I ortype II diabetes may include an alleviation of symptoms or halting theprogression of the disease, as measured by a decrease in serum glucoseor insulin levels in, for example, hyperinsulinemic or hyperglycemicpatients.

[0144] The present invention, thus generally described, will beunderstood more readily by reference to the following examples, whichare provided by way of illustration and are not intended to be limitingof the present invention.

EXAMPLES

[0145] The following abbreviations are used throughout the Examples:

[0146] ACN:Acetonitrile

[0147] DCM:Dichloromethane

[0148] DIEA:Diisopropylethylamine

[0149] DM F: Dimethylformamide

[0150] DMSO:Dimethylsulfoxide

[0151] EDCl:1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride

[0152] HCl:Hydrochloric acid

[0153] HPLC:High Pressure Liquid Chromatography

[0154] KOH:Potassium hydroxide

[0155] MeOH:Methanol

[0156] PyBOP: Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate

[0157] TFA:Trifluoroacetic acid

[0158] THF:Tetrahydrofuran

[0159] TMOF:Trimethylorthoformate

Example 1 Preparation of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0160] Step 1. Preparation of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0161] To a mixture of 2-(2,4-dichlorophenyl)ethylamine (20.2 mmol),4-azidobenzoic acid (22.2 mmol) and EDCl (22.2 mmol) in THF was addedDIEA (40.2 mmol) at room temperature. The mixture was stirred overnightand the THF was removed. The residue was diluted with ethyl acetate,washed with 1N HCl, brine, NaHCO₃ (sat.), and dried over Na₂SO₄ andconcentrated to give a solid, which was purified on silica gel elutingwith ethyl acetate/hexane (1:4) to give[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(93%).

[0162] Step 2. Preparation of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide.

[0163] To a solution of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(2.56 mmol) in THF was added triphenylphosphine (3.07 mmol) at roomtemperature. After 10 minutes, cyclohexyl isocyanate (3.07 mmol) wasadded. The solution was heated at 70° C. overnight. To the mixture wasadded (S)-2-methylpiperazine (5.12 mmol). After being heated at 70° C.for 2 hours, THF was removed. The residue was dissolved in 1N HCl andwater, extracted with ether. The aqueous layer was treated with solidNaHCO₃, extracted with ethyl acetate. The combined ethyl acetate layerswere dried over Na₂SO₄, and concentrated to give a residue, which waspurified via RP-prep-HPLC to give(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas a free base. The base was treated with 1.1 equivalent of HCl (0.5N),dissolved in ACN/water, and lyophilized to give its mono HCl salt.

[0164] HPLC: 23.05 minutes

[0165] MS: MH+=516

Example 2 Preparation of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideon Solid Phase

[0166] An aldehyde Sasrin resin (0.7 mmol/g, 3.5 mmol) was washed withTMOF. To the resin were added TMOF, 2-(2,4-dichlorophenyl)ethylamine(14.0 mmol) and NaH₃B(CN) (20 mmol) in THF. The mixture was shakenovernight, and washed with MeOH and DCM, dried in vacuo to give an amineresin. To the amine resin (2.1 mmol) in DMF was added 4-azidobenzoicacid (10.5 mmol), PyBOP (10.5 mmol) and DIEA (40 mmol). After beingshaken overnight, the resin was washed with MeOH and DCM, dried in vacuoto an amide resin.

[0167] To the amide resin (1.0 g, 0.7 mmol) in THF was addedtriphenylphosphine (7 mmol) followed with cyclohexyl isocyanate. Themixture was heated at 70° C. for 5 hours, and washed with DCM and THF.(S)-2-methylpiperazine (20 mmol) and THF were added. The mixture wasshaken at room temperature overnight, washed with DCM, MeOH and DCM, anddried in vacuo. The resin was treated with TFA for 2 hours. After beingwashed with DCM, the combined solution was concentrated, and purifiedvia HPLC to give(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its bis-trifluoroacetate salt.

[0168] HPLC: 23.05 minutes

[0169] MS: MH+=516

Example 3 Preparation of[4-({[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-cyclohexylvinyl]amino}methyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideon Solid Phase

[0170] An aldehyde Sasrin resin (0.7 mmol/g, 3.5 mmol) was washed withTMOF. To the resin were added TMOF, 2-(2,4-dichlorophenyl)ethylamine (14mmol) and NaH₃B(CN) (1M in THF, 20 mmol). The mixture was shakenovernight, and washed with MeOH and DCM, dried in vacuo to give an amineresin.

[0171] To the amine resin (1.4 mmol) in DMF was added4-bromomethylbenzoic acid (7.0 mmol), PyBOP (7 mmol) and DIEA (28 mmol).After being shaken for 3 hours, the resin was washed with MeOH and DCM,and DMSO. To the resin in DMSO was added sodium azide (14 mmol), and themixture was shaken for 4 days, and washed with water, MeOH, DCM, water,MeOH, DCM and dried.

[0172] To the amide resin (0.14 mmol) in THF was addedtriphenylphosphine (0.382 mmol) followed with cyclohexyl isocyanate. Themixture was heated at 70° C. for 5 hours, and washed with DCM and THF.(S)-2-methylpiperazine (1 mmol) and THF were added. The mixture washeated at 70° C. overnight, washed with DCM, MeOH and DCM, treated withTFA for 2 hours. After being washed with DCM, the combined solution wasconcentrated, and purified via HPLC to give [4-({[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-cyclohexylvinyl]amino}-methyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its bis-trifluoroacetate salt.

[0173] HPLC: 24.07 minutes

[0174] MS: MH+=530

Example 4 Preparation of (4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideon Immobilized Triphenylphosphine Resin

[0175] Step 1. Preparation of Immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0176] To a suspension of triphenylphosphine resin (3 mmol/g, 30 mmol)in THF at 0° C. was added solid[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(30.0 mmol) in several portions. After 30 minutes, the ice-bath wasremoved. The mixture was stirred at room temperature for 3 hours,filtered and washed with DCM, and dried in vacuo to give immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0177] Step 2. Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-cyclohexyl-vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide.

[0178] To polymer-bound phosphine-imine (1.5 mmol/g, 0.15 mmol) in THFin a vial was added cyclohexylisocyanate (0.15 mmol). The vial wascapped and heated at 70° C. overnight. After being cooled to roomtemperature, cis-2,6-dimethylpiperazine (0.18 mmol, 1.2 equivalents) wasadded. The vial was capped and heated at 70° C. for 2 hours, filteredand washed with DCM. The combined filtrates were concentrated, andpurified on HPLC to give(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamideas its bis-trifluoroacetate salt.

[0179] HPLC: 23.79 minutes

[0180] MS: MH+=530

Example 5

[0181] Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0182] Step 1. Preparation of Cycloheptanisocyanate.

[0183] To a cold solution of cycloheptylamine (221 mmol) and charcoal(catalytic) in ethyl acetate at −10° C. was added a pre-cooled solutionof diphosgene (265.0 mmol) in ethyl acetate dropwise via additionfunnel. After the addition, the reaction was heated to reflux overnight,and filtered through a Celite plug. The solution was concentrated togive a thick oil, which was distilled to yield cycloheptanisocyanate asa clear liquid (67%).

[0184] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide.

[0185] To the polymer bound phosphine imine resin (0.194 mmol) in THFwas added cycloheptanisocyanate (194 mmol) and the reaction was heatedat 70° C. overnight. To the reaction was added (S)-2-methylpiperazine(0.23 mmol), and the reaction was heated for 2 hours at 70° C. The resinwas filtered and washed with dichloromethane twice. The filtratesolution was concentrated, and purified via HPLC to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cycloheptylvinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas a white powder.

[0186] HPLC: 23.18 minutes

[0187] MS: MH+=530

Example 6 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0188] To the solution of polymer bound phosphine imine resin (0.21mmol) in THF (2 mL) was added cycloheptylisocyanate (0.21 mmol). Thereaction was heated at 70° C. overnight. To the reaction was added2,6-dimethylpiperazine (0.25 mmol) and the reaction was heated for 2hours at 70° C. The resin was filtered and washed with dichloromethanetwice. The filtrate solution was concentrated, and purified via HPLC togive(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichloro-phenyl)ethyl]carboxamideas a white powder.

[0189] HPLC: 23.70 minutes

[0190] MS: MH+=544.3

Example 7 Preparation of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0191] Step 1. Preparation of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichloro-phenyl)ethyl]carboxamide.

[0192] To a solution of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(0.18 mmol) in THF (2 mL) was added triphenylphosphine (0.21 mmol), andthe mixture was stirred at room temperature for 10 minutes.

[0193] Step 2. Preparation of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-ethyl-cyclo-hexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide.

[0194] To the{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution was added 2-methylcyclohexyl isocyanate (0.25 mmol). Thesolution was heated at 70° C. overnight. To half of the carboimidesolution was added a THF solution of (S)-2-methylpiperazine (0.3 mmol).After being heated at 70° C. for 2 hours, the residue was subjected toHPLC purification to give (4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methylcyclohexyl)-vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0195] HPLC: 24.43 minutes

[0196] MS: MH+=530

Example 8 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0197] To a solution of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(2.0 mmol) in THF was added triphenylphosphine (2.2 mmol), and theresulting mixture was stirred at room temperature for 10 minutes. To the{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamidesolution was added 2-methylcyclohexyl isocyanate (2.4 mmol). Thesolution was heated at 70° C. overnight. To the carboimide solution wasadded 2,6-dimethylpiperazine (2.4 mmol). After being heated at 70° C.for 2 hours, the residue was subjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methylcyclohexyl)-vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0198] HPLC: 24.00 minutes

[0199] MS: MH+=544

Example 9 Preparation of[4-({1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-[4-(tert-butyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0200] Step 1. Preparation of 4-(tert-butyl)cyclohexanisocyanate.

[0201] A pre-cooled solution of diphosgene (168.0 mmol) in ethyl acetatewas added dropwise via addition funnel into the cold solution of4-(t-butyl)cyclohexylamine (140.0 mmol) and charcoal (catalytic) inethyl acetate at −10C. After the addition, the reaction was heated toreflux overnight, and filtered through a Celite plug. The solution wasconcentrated to give a thick oil, which was distilled in vacuo to yield4-(tert-butyl)cyclohexanisocyanate as a clear liquid (48%).

[0202] Step 2. Preparation of[4-({1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-[4-(tert-butyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide.

[0203] To the polymer bound phosphineimine resin (0.150 mmol) in THF wasadded 4-(tert-butyl)cyclohexanisocyanate (0.15 mmol) and the reactionwas heated at 70° C. overnight. To the reaction was added(S)-2-methylpiperazine (0.18 mmol), and reaction was heated for 2 hoursat 70° C. The resin was filtered and washed with dichloromethane twice.The filtrate solution was concentrated, and purified via HPLC to give[4-({1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-[4-(tert-butyl)cyclohexyl]-vinyl}amino)-phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamideas a white powder.

[0204] HPLC: 26.82 minutes

[0205] MS: MH+=572

Example 10 Preparation of[4-({(1Z)-2-aza-2-[4-(tert-butyl)cyclohexyl]-1-(3,5-dimethylpiperazinyl)vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0206] To the polymer bound phosphineimine resin (0.150 mmol) in THF wasadded 4-(tert-butyl)cyclohexanisocyanate (0.15 mmol). The reaction wasthen heated at 70° C. overnight. To the reaction was added2,6-dimethylpiperazine (0.18 mmol), and the reaction was heated for 2hours at 70° C. The resin was filtered and washed with dichloromethanetwice. The filtrate solution was concentrated, and purified via HPLC togive[4-({(1Z)-2-aza-2-[4-(tert-butyl)cyclohexyl]-1-(3,5-dimethylpiperazinyl)vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideas a white powder.

[0207] HPLC: 27.05 minutes

[0208] MS: MH+=586.5

Example 11 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(3,3,5-trimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0209] Step 1. Preparation of 3,3,5-trimethylcyclohexanisocyanate.

[0210] A pre-cooled solution of diphosgene (178.3 mmol) in ethyl acetatewas added dropwise via addition funnel into the cold solution of3,3,5-trimethylcyclohexylamine (148.6 mmol) and charcoal (catalytic) inethyl acetate at −10° C. After the addition, the reaction was heated toreflux overnight, and filtered through a Celite plug. The solution wasconcentrated to give a thick oil, which was distilled in vacuo to yield3,3,5-trimethylcyclohexanisocyanate as a clear liquid (56%).

[0211] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(3,3,5-trimethyl-cyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide.

[0212] To the polymer bound phosphineimine resin (0.15 mmol) in THF wasadded 3,3,5-trimethylcyclohexanisocyanate (0.15 mmol). The reaction washeated at 70° C. overnight. To the reaction was added(S)-2-methylpiperazine (0.18 mmol), and reaction was heated for 2 hoursat 70° C. The resin was filtered and washed with dichloromethane twice.The filtrate solution was concentrated, and purified via HPLC to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(3,3,5-trimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideas a white powder.

[0213] HPLC: 25.62 minutes

[0214] MS: MH+=558.5

Example 12 Preparation of (4{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(3,3,5-trimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0215] To the polymer bound phosphineimine resin (0.150 mmol) in THF wasadded 3,3,5-trimethylcyclohexanisocyanate (0.15 mmol) and the reactionwas heated at 70° C. overnight. To the reaction was added2,6-dimethylpiperazine (0.18 mmol), and the reaction was heated for 2hours at 70° C. The resin was filtered and washed with dichloromethanetwice. The filtrate solution was concentrated, and purified via HPLC togive(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-(3,3,5-trimethylcyclohexyl)vinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas a white powder.

[0216] HPLC: 25.74 minutes

[0217] MS: MH+=572.5

Example 13 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0218] Step 1. Preparation of cyclohex-3-en-isocyanate.

[0219] A solution of 3-cyclohexenylcarboxylic acid (1 mmol),diphenylphosphoryl azide (1.2 mmol) and triethylamine (2.5 mmol) intoluene was heated at 100° C. for 9 hours.

[0220] Step 2. Preparation of[4-(1,3-diaza-3-cyclohex-3-enylpropa-1,2-dienyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0221] To the isocyanate solution prepared above was added immobilized[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide onSasrin resin (0.24 mmol). The mixture was heated at 70° C. for 6 hours,and then washed with DCM.

[0222] Step 3. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0223] To the imine resin in THF was added a THF solution of(S)-2-methylpiperazine (0.5 mmol). After being heated at 70° C. for 2hours, the resin was washed with MeOH/DCM, DCM, and treated with TFA for2 hours. The filtrate was concentrated and subjected to HPLCpurification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0224] HPLC: 22.70 minutes

[0225] MS: MH+=514

Example 14 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0226] To the[4-(1,3-diaza-3-cyclohex-3-enylpropa-1,2-dienyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideresin in THF (2 mL) was added a THF solution of 2,6-dimethylpiperazine(0.5 mmol). After being heated at 70° C. for 2 hours, the resin waswashed with MeOH/DCM (5×), DCM (2×), and treated with TFA for 2 hours.The filtrate was concentrated and subjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0227] HPLC: 23.18 minutes

[0228] MS: MH+=528

Example 15 Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-3,3-dimethylbut-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0229] To a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.05 mmol), was added t-butylisocyanate (14 μL, 0.12 mmol). Thesolution was heated at 70° C. overnight. To the solution was added a THFsolution of 2,6-dimethylpiperazine (1 M, 0.1 mL, 0.1 mmol). After beingheated at 70° C. for 2 hours, the solution was subjected to HPLCpurification to give (4-{[(lZ)-2-aza-1-(cis-3,5-dimethylpiperazinyl)3,3-dimethylbut-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide asits TFA salt.

[0230] HPLC: 27.05 minutes

[0231] MS: MH+=504

Example 16 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0232] Step 1. Preparation of[4-(1,3-diaza-4-cyclohexylbuta-1,2-dienyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0233] To a{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution (0.15 mmol) was added cyclohexylmethylthioisocyanate (0.18mmol). The solution was heated at 80° C. overnight, and used withoutfurther purification.

[0234] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0235] To the[4-(1,3-diaza-4-cyclohexylbuta-1,2-dienyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution (0.075 mmol) was added a THF solution of (S)-2-methylpiperazine(0.15 mmol). After being heated at 70° C. for 2 hours, the solution wassubjected to HPLC purification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0236] HPLC: 24.26 minutes

[0237] MS: MH+=530

Example 17 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0238] To the[4-(1,3-diaza-4-cyclohexylbuta-1,2-dienyl)phenyl]-N-[2-(2,4-dichloro-phenyl)ethyl]carboxamidesolution (0.075 mmol) was added a THF solution of 2,6-dimethylpiperazine(0.15 mmol). After being heated at 70° C. for 2 hours, the solution wassubjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0239] HPLC: 24.68 minutes

[0240] MS: MH+=544

Example 18 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0241] Step 1. Preparation of Cyclooctanisocyanate.

[0242] A pre-cooled solution of diphosgene (236 mmol) in ethyl acetatewas added dropwise via an addition funnel into the cold solution ofcyclooctylamine (196 mmol) and charcoal (catalytic) in ethyl acetate at−10° C. After the addition, the reaction was heated to reflux overnight,and filtered through a Celite plug. The solution was concentrated togive a thick oil, which was distilled in vacuo to yieldcyclooctanisocyanate (46%) as a clear liquid.

[0243] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclooctylvinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0244] To the polymer bound phosphineimine resin (0.15 mmol) in THF wasadded cyclooctanisocyanate (0.15 mmol) and the reaction was heated at70° C. overnight. To the reaction was added (S)-2-methylpiperazine (0.18mmol), and reaction was heated for 2 hours at 70° C. The resin wasfiltered and washed with dichloromethane twice. The filtrate solutionwas concentrated, and purified via HPLC to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas a white powder.

[0245] HPLC: 24.59 minutes

[0246] MS: MH+=544

Example 19 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0247] To the polymer bound phosphineimine resin (0.150 mmol) in THF wasadded cyclooctanisocyanate (0.15 mmol) and the reaction was heated at70° C. overnight. To the reaction was added 2,6-dimethylpiperazine (0.18mmol), and the reaction was heated for 2 hours at 70° C. The resin wasfiltered and washed with dichloromethane twice. The filtrate solutionwas concentrated, and purified via HPLC to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas a white powder.

[0248] HPLC: 24.80 minutes

[0249] MS: MH+=558.5

Example 20 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0250] Step 1. Preparation 4-methylcyclohexanisocyanate.

[0251] A pre-cooled solution of diphosgene (530 mmol) in ethyl acetatewas added dropwise via addition funnel into the cold solution of4-methylcyclohexylamine (442 mmol) and charcoal (catalytic) in ethylacetate at −10° C. After the addition, the reaction was heated to refluxovernight, and filtered through a Celite plug. The solution wasconcentrated to give a thick oil, which was distilled in vacuo to yield(48%) as a clear liquid.

[0252] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclo-hexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide.

[0253] To the polymer bound phosphineimine resin (0.15 mmol) in THF wasadded 4-methylcyclohexanisocyanate (0.15 mmol) and the reaction washeated at 70° C. overnight. To the reaction was added(S)-2-methylpiperazine (0.18 mmol), and reaction was heated for 2 hoursat 70° C. The resin was filtered and washed with dichloromethane twice.The filtrate solution was concentrated, and purified via HPLC to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide as awhite powder.

[0254] HPLC: 23.97 minutes

[0255] MS: MH+=530.5

Example 21 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0256] To the polymer bound phosphineimine resin (0.150 mmol) in THF wasadded 4-methylcyclohexanisocyanate (0.15 mmol), and the reaction washeated at 70° C. overnight. To the reaction was added2,6-dimethylpiperazine (0.18 mmol), and reaction was heated for 2 hoursat 70° C. The resin was filtered and washed with dichloromethane twice.The filtrate solution was concentrated, and purified via HPLC to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide (amixture of cis and trans isomers) as a white powder.

[0257] HPLC: 24.28 minutes (32.6%) and 24.46 minutes (67.3%)

[0258] MS: MH+=544.5

Example 22 Preparation of[4-(1,3-diaza-3-bicyclo[2.2.1]hept-2-ylpropa-1,2-dienyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0259] To a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(0.1 mmol) was added bicyclo[2.2.1]heptan-2-isothiocyanate (0.12 mmol).The mixture was heated at 90° C. for 24 hours to give a phosphoraneimine solution.

Example 23 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0260] To half of the phosphorane imine solution prepared from Example22 was added (S)-2-methylpiperazine (0.2 mmol). The reaction was heatedat 70° C. for 2 hours. The mixture was concentrated and subjected toHPLC purification to give (4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-ylvinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0261] HPLC: 23.26 minutes

[0262] MS: MH+=528

Example 24 Preparation of(4-{[(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-yl-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0263] To half of the phosphorane imine solution prepared above (Example22) was added 2,6-dimethylpiperazine (1 M in THF, 0.2 mL, 0.2 mmol). Thereaction was heated at 70° C. for 2 hours. The mixture was concentratedand subjected to HPLC purification to give(4-{[(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-yl-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0264] HPLC: 23.71 minutes

[0265] MS: MH+=542

Example 25 Preparation of(4-{[2-(trans-2-ethylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0266] Step 1. Preparation of 2-ethyl-1-(hydroxyimino)cyclohexane.

[0267] To a solution of 2-ethylcyclohexanone (104.3 mmol) in water andethanol, and sodium acetate (125.1 mmol) were added hydroxylaminehydrochloride (156.4 mmol), the reaction was heated at 70° C. overnight.The ethanol was removed under reduced pressure, and the reaction mixturewas dissolved in water. The aqueous layer was extracted with ether, andthe combined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated to give 2-ethyl-1-(hydroxyimino)cyclohexane(52%) as a thick oil.

[0268] Step 2. Preparation of 2-ethylcyclohexylamine.

[0269] To the solution of 2-ethyl-1-(hydroxyimino)cyclohexane (6.8 g,48.5 mmol) in ethanol (75 mL) were added sodium pieces (about 8.0 g) inportions, and the reaction was heated to reflux at 110° C. overnight.More sodium pieces were added, and the reaction was stirred for another6 hours. The reaction was treated with concentrated HCl (12 M, 4.0 mL)in water (25 mL). Ethanol was removed in vacuo. The aqueous layer waswashed with ether (10 mL), and treated with aqueous KOH (25 mL) andextracted with ether (3×20 mL). The combined organic extracts werewashed with brine (20 mL), dried over sodium sulfate, and concentratedin vacuo to give 2-ethylcyclohexylamine as an off-white oil.

[0270] Step 3. Preparation of 2-ethylcyclohexylisocyanate.

[0271] To a solution of 2-ethylcyclohexylamine (0.61 mmol) in methanolwas added HCl (4.0 M in dioxane, 0.152 mL), and concentrated to give aresidue. Phosgene solution (20% in toluene, 6.0 mL) was added, and thereaction was heated at 110° C. overnight. Toluene and excess of phosgenewere removed in vacuo to give a residue.

[0272] Step 4. Preparation of(4-{[2-(trans-2-ethylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0273] To a solution of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(0.785 mmol) in THF was added triphenylphosphine (0.785 mmol). Thesolution was stirred for 10 minutes and added totrans-2-ethylcyclohexylisocyanate as prepared above. The solution washeated at 70° C. overnight. 2,6-dimethylpiperazine (0.785 mmol) wasadded, and the reaction was heated for 3 hours at 70° C. The solutionwas concentrated, and purified via HPLC to give(4-{[2-(trans-2-ethylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamideas a white powder.

[0274] HPLC: 24.60 minutes

[0275] MS: MH+=558.3

Example 26 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-cyclohexylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0276] Step 1. Preparation of 2-cyclohexylcyclohexanisocyanate.

[0277] A solution of 2-cyclohexylcyclohexylamine (1.0 mmol) in methanolwas treated with HCl (4 N in dioxane, 0.5 mL, 2 mmol), and concentratedto give a residue, which was treated with phosgene, and heated at 110°C. overnight. Toluene and excess of phosgene were removed in vacuo togive a residue.

[0278] Step 2. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-cyclohexylcyclohexyl)-vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0279] To the isocyanate residue was added a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideprepared in situ from[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.6 mmol) and triphenylphosphine (0.6 mmol) in THF (10 mL). Thesolution was heated for 70° C. overnight. To half of the solution wasadded (S)-2-methylpiperazine (0.5 mmol) and the reaction was heated at70° C. for 2 hours. The mixture was concentrated and subjected to HPLCpurification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-cyclohexylcyclohexyl)-vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0280] HPLC: 27.79 minutes

[0281] MS: MH+=598

Example 27 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-cyclohexylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0282] To half of the{4-[1,3-diaza-3-(2-cyclohexylcyclohexyl)propa-1,2-dienyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution prepared above was added 2,6-dimethylpiperazine (0.5 mmol), andthe mixture was heated at 70° C. for 2 hours. The mixture wasconcentrated and subjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-cyclohexylcyclohexyl)vinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0283] HPLC: 28.52 minutes

[0284] MS: MH+=612

Example 28 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0285] Step 1. Preparation of 1-(hydroxyimino)-2-methoxycyclohexane.

[0286] A mixture of 2-methoxycyclohexanone (39.0 mmol), hydroxylaminehydrochloride (72 mmol), and sodium acetate (48.8 mmol) in ethanol andwater was heated at 70° C. overnight. Ethanol was removed, and theresidue was dissolved in water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried, and concentrated to give1-(hydroxyimino)-2-methoxycyclohexane.

[0287] Step 2. Preparation of 2-methoxycyclohexylamine.

[0288] A mixture of 1-(hydroxyimino)-2-methoxycyclohexane (1.05 mmol)and Raney Nickel (0.5 g) in ethanol (30 mL) was hydrogenated (90 psi) atroom temperature for 2 days. The mixture was filtered through a pad ofCelite, washed with MeOH, and concentrated. The residue was dissolved inMeOH, treated with HCl (4 N in dioxane, 4 mmol), and concentrated togive 2-methoxycyclohexylamine hydrochloride.

[0289] Step 3. Preparation of 2-methoxycyclohexanisocyanate.

[0290] A mixture of methoxycyclohexylamine hydrochloride (0.84 mmol) anda phosgene solution (20% in toluene) was heated at 110° C. overnight.Toluene and excess phosgene were removed in vacuo to give a residue.

[0291] Step 4. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0292] To the isocyanate residue was added a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideprepared in situ from[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.3 mmol) and triphenylphosphine (0.3 mmol) in THF. The solution washeated for 70° C. overnight. To half of the solution was added(S)-2-methylpiperazine (26 mg, 0.25 mmol), and the mixture was heated at70° C. for 2 hours. The mixture was concentrated and subjected to HPLCpurification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methoxycyclohexyl)vinyl]amino}-phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(a mixture of cis and trans isomers) as its TFA salt.

[0293] HPLC: 23.10 and 23.25 minutes

[0294] MS: MH+=546

Example 29 Preparation of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0295] To half the{4-[1,3-diaza-3-(2-methoxycyclohexyl)propa-1,2-dienyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution prepared above was added 2,6-dimethylpiperazine (28 mg, 0.25mmol), and the mixture was heated at 70° C. for 2 hours. The mixture wasconcentrated and subjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(a mixture of cis and trans isomers) as its TFA salt.

[0296] HPLC: 23.44 and 23.66 minutes

[0297] MS: MH+=560

Example 30 Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-perhydro-2H-pyran-4-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0298] Step 1. Preparation of 4-(hydroxyimino)-3,5,6-trihydro-2H-pyran.

[0299] A mixture of 3,5,6-trihydro-2H-pyran-4-one (50 mmol),hydroxylamine hydrochloride (72 mmol), and sodium acetate (61 mmol) inethanol was heated at 70° C. overnight. Ethanol was removed in vacuo.The residue was dissolved in water and ethyl acetate. The aqueous layerwas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give4-(hydroxyimino)-3,5,6-trihydro-2H-pyran (88%).

[0300] Step 2. Preparation of perhydro-2H-pyran-4-ylamine Hydrochloride.

[0301] A mixture of 4-(hydroxyimino)-3,5,6-trihydro-2H-pyran (43.4 mmol)and Raney Nickel (200 mg) in ethanol was hydrogenated (90 psi) at roomtemperature for 3 days. The mixture was filtered through a pad ofCelite, washed with MeOH, and concentrated. The residue was dissolved inMeOH, and treated with HCl (4 N in dioxane, 60 mmol), and concentratedto give perhydro-2H-pyran-4-ylamine hydrochloride (89%).

[0302] Step 3. Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-perhydro-2H-pyran-4-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0303] A mixture of perhydro-2H-pyran-4-ylamine hydrochloride (0.5 mmol)and a phosgene solution (20% in toluene, 4 mL) was heated at 110° C.overnight. Toluene and excess phosgene were removed in vacuo. To theresidue was added a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideprepared in situ from[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.3 mmol) and triphenylphosphine (0.3 mmol) in THF. The solution washeated for 70° C. for 4 hours. To the solution was addedcis-2,6-dimethylpiperazine (0.5 mmol) and heated at 70° C. for 2 hours.The mixture was concentrated and subjected to HPLC purification to give(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-perhydro-2H-pyran-4-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0304] HPLC: 20.50 minutes

[0305] MS: MH+=532.2

Example 31 Preparation of(4-{[2-(trans-2-phenylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0306] Step 1. Preparation of 2-phenylcyclohexyloxime.

[0307] To a solution of 2-phenylcyclohexanone (28.6 mmol) in water andethanol, and sodium acetate (34.4 mmol) was added hydroxylaminehydrochloride (43.0 mmol). The reaction was heated at 70° C. overnight,and ethanol was removed under reduced pressure. The reaction mixture wasdissolved in water and extracted with ether. The combined organicextracts were washed with brine, dried over sodium sulfate, andconcentrated to give 2-phenylcyclohexyloxime (92%) as a fluffy whitepowder.

[0308] Step 2. Preparation of trans-2-phenylcyclohexylamine.

[0309] To a solution of trans-2-phenylcyclohexyloxime (7.92 mmol) inethanol were added sodium pieces (about 3.0 g in portions). The reactionwas heated to reflux at 110° C. overnight. More sodium pieces were addedand the reaction was further stirred for another 6 hours. The reactionmixture was treated with concentrated HCl in water, and ethanol wasremoved in vacuo. The aqueous layer was extracted with ether andneutralized with aqueous KOH. The aqueous layer was treated with ether.The ether layers were washed with brine, dried over sodium sulfate, andconcentrated in vacuo to give 2-phenylcyclohexylamine as a brown oil.

[0310] Step 3. Preparation of trans-2-phenylcyclohexylisocyanate.

[0311] To a solution of 2-phenylcyclohexylamine (2.28 mmol) in methanolwas added HCl (4.0 M in dioxane, 0.57 mL). The solution was concentratedand treated with phosgene solution (20% in toluene, 16.0 mL). Thereaction was heated at 110° C. overnight and concentrated in vacuo.

[0312] Step 4. Preparation of(4-{[2-(trans-2-phenylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethyl-piperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethy]carboxamide.

[0313] To a solution of[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.149 mmol) in THF was added triphenylphosphine (0.149 mmol). Themixture was stirred for 10 minutes and transferred to 2-phenylcyclohexylisocyanate (about 100 mg) as prepared above. The reaction was heated at70° C. overnight. 2,6-dimethylpiperazine (0.149 mmol) was added, and thereaction was heated 3 hours at 70° C. The solution was concentrated, andpurified via HPLC to give(4-{[2-(trans-2-phenylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas an off-white powder.

[0314] HPLC: 24.86 minutes

[0315] MS: MH+=606.63

Example 32 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0316] Step 1. Preparation of 4-methoxycyclohexanisocyanate.

[0317] To a solution of 4-methoxycyclohexanecarboxylic acid (2.0 mmol),in DCM was added oxalyl chloride and two drops of DMF. After 1 hour, DCMand excess oxalyl chloride were removed, and the produce was pumped onfor 10 minutes. The residue was dissolved in acetone and added to asolution of sodium azide (0.3 g) in water at 0° C. The mixture wasstirred at room temperature for 30 minutes and then diluted withchloroform. The organic layer was washed with brine, dried over Na₂SO₄,and concentrated to 10 mL. The solution was heated at 90° C. for 30minutes, concentrated, and dissolved in THF (4 mL).

[0318] Step 2. Preparation of{4-[1,3-diaza-3-(4-methoxycyclohexyl)propa-1,2-dienyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0319] To a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,prepared in situ from[4-(azadiazomvinyl)-phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.3 mmol) and triphenylphosphine (0.3 mmol) in THF, was added the4-methoxycyclohexanisocyanate THF solution prepared above. The solutionwas heated at 70° C. overnight.

[0320] Step 3. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0321] To the carbodiimide solution (0.15 mmol) from Step 2, was added(S)-2-methylpiperazine (0.25 mmol). The solution was heated at 70° C.for 2 hours, and subjected to HPLC purification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2aza-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide(a mixture of cis and trans isomers) as its TFA salt.

[0322] HPLC: 21.34 and 21.95 minutes

[0323] MS: MH+=546

Example 33 Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0324] To a{4-[1,3-diaza-3-(4-methoxycyclohexyl)propa-1,2-dienyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidesolution (0.15 mmol) was added 2,6-dimethylpiperazine (0.25 mmol). Thesolution was heated at 70° C. for 2 hours, and subjected to HPLCpurification to give(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-{[2-(2,4-dichlorophenyl)-ethyl]carboxamide(a mixture of cis and trans isomers) as its TFA salt.

[0325] HPLC: 21.64 and 22.24 minutes

[0326] MS: MH+=560

Example 34 Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0327] Step 1. Preparation of 1-(hydroxyimino)-4-phenylcyclohexane.

[0328] A mixture of 4-phenylcyclohexanone (28.7 mmol), hydroxylaminehydrochloride (36.0 mmol), and sodium acetate (60.95 mmol) in ethanoland water was heated at 70° C. overnight. Ethanol was removed, and theresidue was dissolved in water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried, and concentrated to give1-(hydroxyimino)-4-phenylcyclohexane (97%).

[0329] Step 2. Preparation of 4-phenylcyclohexylamine.

[0330] A mixture of 1-(hydroxyimino)-4-phenylcyclohexane (17.4 mmol) andRaney Nickel (300 mg) in ethanol was hydrogenated (90 psi) at 50° C. for40 hours. The mixture was filtered through a pad of Celite, washed withMeOH, and concentrated. The residue was dissolved in MeOH, treated withHCl (4 N in dioxane, 20 mmol), and concentrated to give4-phenylcyclohexylamine hydrochloride (100%).

[0331] Step 3. Preparation of 4-phenylcyclohexanisocyanate.

[0332] A mixture of 4-phenylcyclohexylamine hydrochloride (0.5 mmol) anda phosgene solution (20% in toluene, 4 mL) was heated at 110° C.overnight. Toluene and excess phosgene were removed in vacuo to give aresidue.

[0333] Step 4. Preparation of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.

[0334] To the isocyanate residue was added a solution of{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamideprepared in situ from[4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)-ethyl]carboxamide(0.3 mmol) and triphenylphosphine (0.3 mmol) in THF. The solution washeated for 70° C. overnight. To half of the solution was added(S)-2-methylpiperazine (0.25 mmol), and the mixture was heated at 70° C.for 2 hours. The mixture was concentrated and subjected to HPLCpurification to give(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0335] HPLC: 26.37 minutes

[0336] MS: MH+=592

Example 35 Preparation of(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0337] To half of the solution prepared above (Example 34) was addedcis-2,6-dimethylpiperazine (0.25 mmol), and the mixture was heated at70° C. for 2 hours. The mixture was concentrated and subjected to HPLCpurification to give(4-{[(1Z)-2-aza-1-(cis-3,5-dimethylpiperazinyl)-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamideas its TFA salt.

[0338] HPLC: 26.52 minutes

[0339] MS: MH+=606

Example 36 General Procedure for the Preparation of Polystyrene-Bound4-hydroxy-2-methoxybenzaldehyde.

[0340] Merrifield resin (1 equivalent) was soaked inN-methylpyrrolidinone (NMP) for 5 minutes, after which time, 2equivalents of 4-hydroxy-2-methoxybenzaldehyde and K₂CO₃ (2 equivalents)were added. The resulting mixture was degassed with argon and heated at120° C. for 18 hours with shaking. The resin was filtered and washedwith DMF, H₂O, MeOH and CH₂Cl₂. The beads were then dried overnightunder vacuum to yield resin-bound 4-hydroxy-2-methoxybenzaldehyde.

Example 37 General Procedure for the Preparation of Polystyrene-BoundAmines.

[0341] Resin-bound 4-hydroxy-2-methoxybenzaldehyde (1 equivalent) wastreated with 10 equivalents of a primary amine in (MeO)₃CH for 18 hoursat 23° C. with shaking. The resin-bound imine was rinsed quickly (3 ×)with anhydrous CH₂Cl₂. The resin-bound imine was immediately reducedusing pyridine-borane complex (5 equivalents) in a solution ofCH₂Cl₂:MeOH:AcOH (2:2:1) with shaking at 23° C. for 18 hours. Theresulting resin-bound amine was washed with CH₂Cl₂, MeOH, Et₃N andCH₂Cl₂ and dried overnight under vacuum.

Example 38 General Procedure for the Preparation of Polystyrene-BoundP-Azidobenzamides.

[0342] A mixture of resin-bound amine (1 equivalent), p-azidobenzoicacid (10 equivalents) and anhydrous CH₂Cl₂ was shaken until most of theacid had dissolved. To this mixture was added DIC (3.3 equivalents), andthe resulting mixture was shaken for 3 hours at 23° C. After this time,the resin was washed with CH₂Cl₂ and anhydrous THF (each wash wasrepeated 3×) and the resin-bound benzamide was dried overnight undervacuum. Example 39

General Procedure for the Preparation of Polystyrene-Bound P-BenzamidoIminophosphoranes.

[0343] To a mixture of resin-bound p-azidobenzamide (1 equivalent) andanhydrous THF was added Ph₃P (10 equivalents) at 23° C. Vigorousbubbling ensued which subsided after about 30 minutes. The resultingmixture was shaken at room temperature for 18 hours, filtered, washedwith anhydrous THF and CH₂Cl₂, and dried under vacuum overnight to yieldresin-bound p-benzamido iminophosphorane.

Example 40 General Procedure for the Preparation of Polystyrene-BoundP-Benzamido Carbodiimides.

[0344] A mixture of resin-bound p-benzamido iminophosphorane (1equivalent) and anhydrous THF was treated with an isocyanate (10equivalents) at 23° C. for 16 hours with shaking. The resin was thenfiltered, washed with anhydrous THF and CH₂Cl₂ and dried under vacuumovernight to yield resin-bound p-benzamido carbodiimide.

Example 41 General Procedure for the Preparation of Polystyrene-BoundP-Benzamido Guanidines.

[0345] A mixture of resin-bound p-benzamdio carbodiimide (1 equivalent)and anhydrous THF was treated with an amine (20 equivalents) for 36hours at 23° C. with shaking. The resin was then filtered, washed withDMF, MeOH and CH₂Cl₂ and dried under vacuum to yield resin-boundp-benzamido guanidine. The desired product was liberated from thepolystyrene support using TFA: CH₂Cl₂ (4:1) at 23° C. for 3 hours withshaking. The resin was filtered, washed with CH₂Cl₂, and the resultingfiltrate was concentrated under reduced pressure to yield p-benzamidoguanidine as the TFA salt.

[0346] The following compounds were synthesized using the generalprocedures described above:

[0347]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-phenylethyl)carboxamide.LC/MS m/z 526.7 (MH+), Rt 3.15 minutes.

[0348]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide.LC/MS m/z 556.8 (MH+), Rt 3.28 minutes.

[0349]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(3-chlorophenyl)ethyl]carboxamide.LC/MS m/z 561.2 (MH+), Rt 3.29 minutes.

[0350]{4-[((1Z)-2-aza-2-cyclohexyl-1-{[(4-fluorophenyl)methyl](2-pyridylmethyl)amino}vinyl)amino]phenyl}-N-(2-phenylethyl)carboxamide.LC/MS m/z 564.7 (MH+), Rt 3.98 minutes.

[0351]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 595.6 (MH+), Rt 3.53 minutes.

[0352]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-ethylphenyl)ethyl]carboxamide.LC/MS m/z 554.8 (MH+), Rt 3.53 minutes.

[0353]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-methoxyphenyl)ethyl]carboxamide.LC/MS m/z 556.8 (MH+), Rt 3.23 minutes.

[0354]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-cyclohex-1-enylethyl)carboxamide.LC/MS m/z 530.8 (MH+), Rt 2.85 minutes.

[0355]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-fluorophenyl)ethyl]carboxamide.LC/MS m/z 544.7 (MH+), Rt 2.02 minutes.

[0356]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-chlorophenyl)ethyl]carboxamide.LC/MS m/z 561.2 (MH+), Rt 2.10 minutes.

[0357]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-bromophenyl)ethyl]carboxamide.LC/MS m/z 605.6 (MH+), Rt 2.20 minutes.

[0358]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methylphenyl)ethyl]carboxamide.LC/MS m/z 540.8 (MH+), Rt 2.10 minutes.

[0359]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-chlorophenyl)ethyl]carboxamide.LC/MS m/z 561.2 (MH+), Rt 2.10 minutes.

[0360] [4-({(1E)-2-aza-1-[({1-[(4-chlorophenyl)methyl]-5-methylimidazol-4-yl}methyl)amino]-2-cyclohexylvinyl}amino)phenyl]-N-[2-(4-methoxyphenyl)ethyl]carboxamide.LC/MS m/z 614.2 (MH+), Rt 2.20 minutes.

[0361]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide.LC/MS m/z 556.8 (MH+), Rt 3.27 minutes.

[0362] (4-{[(1E)-2-aza-2-cyclohexyl-1-(4-methylpiperidyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 516.5 (MH+), Rt 3.35 minutes.

[0363]{4-[((1Z)-2-aza-2-cyclohexyl-1-piperazinylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 503.5 (MH+), Rt 3.33 minutes.

[0364]{4-[((1Z)-2-aza-2-cyclohexyl-1-(1,4-diazaperhydroepinyl)vinyl)amino]-phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 517.5 (MH+), Rt 3.36 minutes.

[0365](4-{[1-(2,5-trans-dimethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 531.5 (MH+), Rt 3.42 minutes.

[0366](4-{[(1Z)-2-aza-1-(2,5-diazabicyclo[4.4.0]dec-2-yl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 557.6 (MH+), Rt 3.52 minutes.

[0367](4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]-amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 517.5 (MH+), Rt 3.36 minutes.

[0368]{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-ethylphenyl)methyl]-amino}-3-methylbut-1-enyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]-carboxamide.LC/MS m/z 583.6 (MH+), Rt 3.58 minutes.

[0369](4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-3-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 547.5 (MH+), Rt 3.25 minutes.

[0370](4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-2-chlorophenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 552.0 (MH+), Rt 3.32 minutes.

[0371](4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-3-methylphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 531.5 (MH+), Rt 3.30 minutes.(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-5-chloro-2-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide.LC/MS m/z 582.0 (MH+), Rt 3.48 minutes.

Example 42 Generic Experimentals for Examples 43-59

[0372] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0373] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered and washedwith dry DCM and the resinimmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidewas dried in vacuo for 8 hours.

[0374] Step 2. Synthesis of Isocyanates from Amine Hydrochlorides

[0375] To 1 g of an amine hydrochloride in a round-bottomed flask fittedwith a reflux condenser was added 6 ml of phosgene solution in toluene(20%), and the suspension heated to reflux (110° C.) till it turnedclear (usually after about 2-8 hours). The solution was cooled andconcentrated in vacuo and the resulting isocyanate was either distilledor used as such.

[0376] Step 3. Synthesis of Isocyanates from Carboxylic Acids

[0377] To 1 mmol of carboxylic acid dissolved in 5 ml of DCM was added 1mmol of triethyl amine and 1 mmol of diphenylphosphorazidate, and thereaction was stirred under nitrogen for 30 minutes at 0° C. and then at50° C. for 3 hours. The reaction was then cooled to room temperature,concentrated in vacuo and then dry THF was added to make up a stocksolution of the isocyanate which was used without further purification.

[0378] Step 4. Synthesis of Carbodiimide

[0379] To resin bound phophinimine (Step 1 above; 1 mmol) suspended indry THF was added 1 mmol of the isocyanate from Steps 2 or 3 above, andthe suspension was stirred for 8 hours at 70° C. in a capped vial.

[0380] Step 5. Synthesis of Guanidine

[0381] The reaction in Step 4 above was cooled to room temperature, 2equivalents of a piperazine were added, and the reaction mixture washeated at 70° C. with stirring for 2 hours and cooled. The reactionmixture was then filtered, washed with THF, and the combined filtratewas concentrated in vacuo and the residue purified by silica gelchromatography, eluting with 10% methanol in DCM with 2% triethyl amine.The final product could be further purified with reversed phase HPLC.

[0382] General Experimental Scheme for Examples 43-59

Example 43 Synthesis of(4-([trans-2-methylcyclohexyl)(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0383] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0384] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered, washed withdry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0385] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0386] To 1 g of trans-2-methylcyclohexylamine hydrochloride(synthesized by hydroboration of 2-methylcyclohexene as described by H.C. Brown et al., Tetrahedron, 43, No.18, 4071-4078 (1987)) in around-bottomed flask fitted with a reflux condenser, was added 6 ml ofphosgene solution in toluene (20%) and the suspension was heated toreflux (110° C.) until it turned clear (usually after about 2-8 hours).The solution was cooled and concentrated in vacuo and the resultingisocyanate was either distilled or used as such.

[0387] Step 3. Synthesis of Carbodiimide

[0388] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above, and the suspension wasstirred for 8 hours at 70° C. in a capped vial.

[0389] Step 4. Synthesis of Guanidine

[0390] The product of step 3 above was cooled to room temperature, 2equivalents of the (S)-(+)-2-methylpiperazine were added, and thereaction mixture was heated at 70° C. with stirring for 2 hours andcooled. The reaction mixture was then filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified with reversephase HPLC.

[0391] HPLC: 7.55 minutes

[0392] MS: MH+=544.5

Example 44 Synthesis of(4-{[1-((3R)-3-methylpiperazinyl)-2-((1S,2S)-2-methylcyclohexyl)(1Z)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0393] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0394] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered, washed withdry DCM and the resinimmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidewas dried in vacuo for 8 hours.

[0395] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0396] To 1 g of trans-2-methylcyclohexylamine hydrochloride(synthesized by hydroboration of 2-methylcyclohexene as described by H.C. Brown et al, Tetrahedron, 43, No.18, 4071-4078(1987)) in around-bottomed flask fitted with a reflux condenser was added 6 ml ofphosgene solution in toluene (20%), and the suspension was heated toreflux (110° C.) until it turned clear (usually after about 2-8 hours).The solution was cooled and concentrated in vacuo, and the resultingisocyanate was either distilled or used as such.

[0397] Step 3. Synthesis of Carbodiimide

[0398] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above, and the suspension wasstirred for 8 hours at 70° C. in a capped vial.

[0399] Step 4. Synthesis of Guanidine

[0400] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of (S)-(+)-2-methylpiperazine were added.The reaction mixture was then heated at 70° C. with stirring for 2 hoursand cooled. The resulting mixture was filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified withreversed phase HPLC.

[0401] HPLC: 7.27 minutes

[0402] MS: MH+=530.5

Example 45 Synthesis(4-{[(1Z)-2-aza-2-(2,6-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0403] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0404] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered, washed withdry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0405] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0406] To 1 g of 2,6-dimethylcyclohexylamine hydrochloride (synthesizedby the reductive amination of 2,6-dimethylcyclohexanone as in SukantaBhattacharyya et al, Synlett., 11, 1781-1783 (1999)) in a round-bottomedflask fitted with a reflux condenser was added 6 ml of phosgene solutionin toluene (20%), and the suspension was heated to reflux (110° C.)until it turned clear (usually after about 2-8 hours). The solution wascooled and concentrated in vacuo and the resulting isocyanate was eitherdistilled or used as such.

[0407] Step 3. Synthesis of Carbodiimide

[0408] To resin bound phosphinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above, and the suspension wasstirred for 8 hours at 70° C. in a capped vial.

[0409] Step 4. Synthesis of Guanidine

[0410] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of the cis-2,6-dimethylpiperazine wereadded. The reaction mixture was then heated at 70° C. with stirring for2 hours and cooled. The resulting mixture was then filtered, washed withTHF, and the combined filtrate was concentrated in vacuo and the residuepurified by silica gel chromatography, eluting with 10% methanol in DCMwith 2% triethyl amine. The final product could be further purified withreversed phase HPLC.

[0411] HPLC: 7.6-7.9 minutes

[0412] MS: MH+=55

Example 46 Synthesis of(4-{[1-((3S,5S)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0413] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0414] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered, washed withdry DCM, and the immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidewas dried in vacuo for 8 hours.

[0415] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0416] To 1 g of an amine hydrochloride in a round-bottomed flask fittedwith a reflux condenser was added 6 ml of phosgene solution in toluene(20%). The suspension was heated to reflux (110° C.) until it turnedclear (usually after about 2-8 hours). The solution was cooled andconcentrated in vacuo, and the resulting isocyanate was either distilledor used as such.

[0417] Step 3. Synthesis of Carbodiimide

[0418] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0419] Step 4. Synthesis of Guanidine

[0420] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of (2S,6S)-2,6-dimethylpiperazine(synthesized as in E. Jon Jacobson et al., J. Org. Chem., 60, 4177-83(1995)) were added and the reaction mixture was heated at 70° C. withstirring for 2 hours and cooled. The reaction mixture was then filtered,washed with THF, and the combined filtrate was concentrated in vacuo andthe residue purified by silica gel chromatography, eluting with 10%methanol in DCM with 2% triethyl amine. The final product could befurther purified with reversed phase HPLC.

[0421] HPLC: 7.3 minutes

[0422] MS: MH+=530.3

Example 47 Synthesis of(4-{[(1Z)-2-aza-2-(2,3-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0423] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0424] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours and then filtered, washed withdry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0425] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0426] To 1 g of 2,3-dimethylcyclohexylamine hydrochloride in around-bottomed flask fitted with a reflux condenser, was added 6 ml ofphosgene solution in toluene (20%). The suspension was then heated toreflux (110° C.) until it turned clear (usually after about 2-8 hours).The solution was cooled and concentrated in vacuo, and the resultingisocyanate was either distilled or used as such.

[0427] Step 3. Synthesis of Carbodiimide

[0428] To resin bound phophinimine (1 mmol) suspended in dry THF, wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0429] Step 4. Synthesis of Guanidine

[0430] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of cis-2,6-dimethylpiperazine were added.The reaction mixture was then heated at 70° C. with stirring for 2 hoursand cooled. The resulting mixture was filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified with reversephase HPLC.

[0431] HPLC: 7.97 minutes

[0432] MS: MH+=558.5

Example 48 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)-2-(trans-2-methylcycloheptyl)(1Z)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0433] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0434] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The reaction mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0435] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0436] To 1 g of trans-2-methylcycloheptylamine hydrochloride(synthesized by hydroboration of 2-methylcycloheptene as described by H.C. Brown et al,

[0437] Tetrahedron, 43, No.18, 4071-4078 (1987)) in a round-bottomedflask fitted with a reflux condenser was added 6 ml of phosgene solutionin toluene (20%). The suspension was then heated to reflux (110° C.)until it turned clear (usually after about 2-8 hours). The solution wascooled and concentrated in vacuo, and the resulting isocyanate waseither distilled or used as such.

[0438] Step 3. Synthesis of Carbodiimide

[0439] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0440] Step 4. Synthesis of Guanidine

[0441] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of the (S)-(+)-2-methylpiperazine wereadded. The reaction mixture was then heated at 70° C. with stirring for2 hours and cooled. The resulting mixture was then filtered, washed withTHF, and the combined filtrate was concentrated in vacuo and the residuepurified by silica gel chromatography, eluting with 10% methanol in DCMwith 2% triethyl amine. The final product could be further purified withreversed phase HPLC.

[0442] HPLC: 7.9 minutes

[0443] MS: MH+=544.3

Example 49 Synthesis of(4-{[1-((3R)-3-methylpiperazinyl)-2-((trans-2-methylcycloheptyl)(1Z)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0444] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0445] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The reaction mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0446] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0447] To 1 g of trans-2methylcycloheptylamine hydrochloride(synthesized by hydroboration of 2-methylcycloheptene as described by H.C. Brown et al, Tetrahedron, 43, No.18, 4071-4078 (1987)) in around-bottomed flask fitted with a reflux condenser, was added 6 ml ofphosgene solution in toluene (20%). The suspension was heated to reflux(110° C.) till it turned clear (usually after about 2-8 hours). Thesolution was cooled and concentrated in vacuo, and the resultingisocyanate was either distilled or used as such.

[0448] Step 3. Synthesis of Carbodiimide

[0449] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0450] Step 4. Synthesis of Guanidine

[0451] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of cis-2,6-dimethylpiperazine were added.The reaction mixture was heated at 70° C. with stirring for 2 hours andcooled. The resulting mixture was then filtered, washed with THF, andthe combined filtrate was concentrated in vacuo and the residue purifiedby silica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified withreversed phase HPLC.

[0452] HPLC: 24.3 minutes

[0453] MS: MH+=558.5

Example 50 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(trans-4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0454] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0455] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resinimmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidewas dried in vacuo for 8 hours.

[0456] Step 2. Synthesis of Isocyanate from Carboxylic Acid

[0457] To 1 mmol of trans-4-methylcyclohexanecarboxylic acid dissolvedin 5 ml of DCM was added 1 mmol of triethyl amine and 1 mmol ofdiphenylphosphorazidate. The resulting mixture was stirred undernitrogen for 30 minutes at 0° C. and then at 50° C. for 3 hours. Theresulting mixture was cooled to room temperature, concentrated in vacuo,and then dry THF was added to make up a stock solution of the isocyanatewhich was used without further purification.

[0458] Step 3. Synthesis of Carbodiimide

[0459] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasstirred for 8 hours at 70° C. in a capped vial.

[0460] Step 4. Synthesis of Guanidine

[0461] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of (S)-(+)-2-methylpiperazine were added.The reaction mixture was heated at 70° C. with stirring for 2 hours andcooled. The resulting mixture was then filtered, washed with THF, andthe combined filtrate was concentrated in vacuo and the residue purifiedby silica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product was further purified with reversedphase HPLC.

[0462] HPLC: 7.59 minutes

[0463] MS: MH+=530.3

Example 51 Synthesis of(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-(trans-4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0464] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0465] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The reaction mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0466] Step 2. Synthesis of Isocyanate from Carboxylic Acid

[0467] To 1 mmol of carboxylic acid dissolved in 5 ml of DCM was added 1mmol of triethyl amine and 1 mmol of diphenylphosphorazidate. Thereaction was then stirred under nitrogen for 30 minutes at 0° C. andthen at 50° C. for 3 hours. The resulting mixture was then cooled toroom temperature, concentrated in vacuo, and then dry THF was added tomake up a stock solution of the isocyanate which was used withoutfurther purification.

[0468] Step 3. Synthesis of Carbodiimide

[0469] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate of step 3. The suspension was stirred for8 hours at 17° C. in a capped vial.

[0470] Step 4. Synthesis of Guanidine

[0471] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of cis-2,6-dimethylpiperazine were added.The reaction mixture was then heated at 70° C. with stirring for 2 hoursand cooled. The resulting mixture was then filtered, washed with THF,and the combined filtrate was concentrated in vacuo and the residuepurified by silica gel chromatography, eluting with 10% methanol in DCMwith 2% triethyl amine. The final product was further purified byreversed phase HPLC.

[0472] HPLC: 7.92 minutes

[0473] MS: MH+=544.3

Example 52 Synthesis of[4-({1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-[4-(trifluoromethyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0474] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0475] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resinimmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamidewas dried in vacuo for 8 hours.

[0476] Step 2. Synthesis of Isocyanate from Carboxylic Acid

[0477] To 1 mmol of carboxylic acid dissolved in 5 ml of DCM was added 1mmol of triethyl amine and 1 mmol of diphenylphosphorazidate. Thereaction was then stirred under nitrogen for 30 minutes at 0° C. andthen at 50° C. for 3 hours. The resulting mixture was then cooled toroom temperature, concentrated in vacuo, and then dry THF was added tomake up a stock solution of the isocyanate which was used withoutfurther purification.

[0478] Step 3. Synthesis of Carbodiimide

[0479] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0480] Step 4. Synthesis of Guanidine

[0481] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents (S)-(+)-2-methylpiperazine were added. Thereaction mixture was then heated at 70° C. with stirring for 2 hours andcooled. The reaction mixture was then filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified withreversed phase HPLC.

[0482] HPLC: 7.59 minutes

[0483] MS: MH+=584.3

Example 53 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(3-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0484] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0485] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The reaction mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0486] Step 2. Synthesis of Isocyanate from Carboxylic Acid

[0487] To 1 mmol of 3-methoxycyclohexanecarboxylic acid dissolved in 5ml of DCM was added 1 mmol of triethyl amine and 1 mmol ofdiphenylphosphorazidate. The reaction mixture was then stirred undernitrogen for 30 minutes at 0° C. and then at 50° C. for 3 hours. Thereaction mixture was then cooled to room temperature, concentrated invacuo, and then dry THF was added to make up a stock solution of theisocyanate which was used without further purification.

[0488] Step 3. Synthesis of Carbodiimide

[0489] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0490] Step 4. Synthesis of Guanidine

[0491] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of (S)-(+)-2-methylpiperazine were added.The reaction mixture was then heated at 70° C. with stirring for 2 hoursand cooled. The resulting mixture was filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product was further purified by reversed phaseHPLC.

[0492] HPLC: 6.95 minutes

[0493] MS: MH+=546.3

Example 54 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)-2-((2S,3S,1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)(1Z)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0494] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2(2,4-dichlorophenyl)ethyl]carboxamide

[0495] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to OC with stirring. 1 mmol of theazide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0496] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0497] To 1 g of (1S,2S,3S,5R)-(+)-isopinocampheylamine hydrochloride ina round-bottomed flask fitted with a reflux condenser, was added 6 ml ofphosgene solution in toluene (20%). The resulting suspension was thenheated to reflux (110° C.) until it turned clear (usually after about2-8 hours). The solution was cooled and concentrated in vacuo, and theresulting isocyanate was either distilled or used as such.

[0498] Step 3. Synthesis of Carbodiimide

[0499] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0500] Step 4. Synthesis of Guanidine

[0501] The reaction product of step 3 above was cooled to roomtemperature and 2 equivalents of the (S)-(+)-2-methylpiperazine wereadded. The reaction mixture was heated at 70° C. with stirring for 2hours and cooled. The resulting mixture was filtered, washed with THF,and the combined filtrate was concentrated in vacuo and the residuepurified by silica gel chromatography, eluting with 10% methanol in DCMwith 2% triethyl amine. The final product could be further purified withreversed phase HPLC.

[0502] HPLC: 8.68 minutes

[0503] MS: MH+=570

Example 55 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2,2-dimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0504] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0505] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0506] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0507] To 0.5 g of 2,2 dimethyl cyclohexamine hydrochloride in around-bottomed flask fitted with a reflux condenser, was added 4.5 ml ofphosgene solution in toluene (20%). The suspension was then heated toreflux (110° C.) until it turned clear (usually after about 2-8 hours).The solution was cooled and concentrated in vacuo, and the resultingisocyanate was either distilled or used as such.

[0508] Step 3. Synthesis of Carbodiimide

[0509] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0510] Step 4. Synthesis of Guanidine

[0511] The reaction product of step 3 above was cooled to roomtemperature and 1.2 equivalents of (S)-(+)-2-methylpiperazine wereadded. The reaction mixture was then heated at 70° C. with stirring for2 hours and cooled. The resulting mixture was filtered, washed with THF,and the combined filtrate was concentrated in vacuo and the residuepurified by silica gel chromatography, eluting with 10% methanol in DCMwith 2% triethyl amine. The final product could be further purified withreversed phase HPLC.

[0512] HPLC: 7.93 minutes

[0513] MS: MH+=544

Example 56 Synthesis of(4-{[(1Z)-2-aza-2-(2,2-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0514] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0515] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The reaction mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0516] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0517] To 0.5 g of 2,2 dimethyl cyclohexamine hydrochloride in around-bottomed flask fitted with a reflux condenser, was added 4.5 ml ofphosgene solution in toluene (20%). The resulting suspension was thenheated to reflux (110° C.) until it turned clear (usually after about2-8 hours). The solution was cooled and concentrated in vacuo, and theresulting isocyanate was either distilled or used as such.

[0518] Step 3. Synthesis of Carbodiimide

[0519] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0520] Step 4. Synthesis of Guanidine

[0521] The reaction product of step 3 above was cooled to roomtemperature and 1.2 equivalents of 2,6-dimethylpiperazine were added.The reaction mixture was then heated at 70° C. with stirring for 2 hoursand cooled. The resulting mixture was filtered, washed with THF, and thecombined filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography, eluting with 10% methanol in DCM with 2%triethyl amine. The final product could be further purified withreversed phase HPLC.

[0522] HPLC: 8.10 minutes

[0523] MS: MH+=558.6

Example 57 Synthesis of(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0524] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0525] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0526] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0527] To 1 g of isopinocampheylamine hydrochloride in a round-bottomedflask fitted with a reflux condenser, was added 8 ml of phosgenesolution in toluene (20%). The resulting suspension was then heated toreflux (110° C.) until it turned clear (usually after about 2-8 hours).The solution was cooled and concentrated in vacuo and the resultingisocyanate was either distilled or used as such.

[0528] Step 3. Synthesis of Carbodiimide

[0529] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasstirred for 8 hours at 70° C. in a capped vial.

[0530] Step 4. Synthesis of Guanidine

[0531] The reaction product of step 3 above was cooled to roomtemperature and 1.2 equivalents of 2,6-dimethylpiperazine were added.The resulting reaction mixture was heated at 70° C. with stirring for 2hours and cooled. The resulting reaction mixture was filtered, washedwith THF, and the combined filtrate was concentrated in vacuo and theresidue purified by silica gel chromatography, eluting with 10% methanolin DCM with 2% triethyl amine. The final product could be furtherpurified with reversed phase HPLC.

[0532] HPLC: 8.83 minutes

[0533] MS: MH+=584.6

Example 58 Synthesis of(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0534] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0535] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0536] Step 2. Synthesis of Isocyanate from Amine Hydrochloride

[0537] To 1 g of isopinocampheylamine hydrochloride in a round-bottomedflask fitted with a reflux condenser was added 8 ml of phosgene solutionin toluene (20%). The resulting suspension was then heated to reflux(110° C.) until it turned clear (usually after about 2-8 hours). Thesolution was cooled and concentrated in vacuo, and the resultingisocyanate was either distilled or used as such.

[0538] Step 3. Synthesis of Carbodiimide

[0539] To resin bound phophinimine (1 mmol) suspended in dry THF wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0540] Step 4. Synthesis of Guanidine

[0541] The reaction product of step 3 above was cooled to roomtemperature and 1.2 equivalents of (S)-(+)-2-methylpiperazine wereadded. The resulting reaction mixture was heated at 70° C. with stirringfor 2 hours and cooled. The resulting mixture was then filtered, washedwith THF, and the combined filtrate was concentrated in vacuo and theresidue purified by silica gel chromatography, eluting with 10% methanolin DCM with 2% triethyl amine. The final product could be furtherpurified with reversed phase HPLC.

[0542] HPLC: 8.73 minutes

[0543] MS: MH+=570.6

Example 59 Synthesis of(4-{[1-((3S,5S)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0544] Step 1. Synthesis ofImmobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide

[0545] 1 mmol of resin bound triphenylphosphine in a round-bottomedflask was suspended in THF and cooled to 0° C. with stirring. 1 mmol ofthe azide([4-(azadiazomvinyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide)was then added slowly in small portions and the flask vented to releasethe evolved nitrogen. After 30 minutes at 0° C., the reaction wasstirred at room temperature for 8 hours. The resulting mixture was thenfiltered, washed with dry DCM, and the resin immobilized{4-[aza(triphenylylidene)methyl]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide was dried in vacuo for 8 hours.

[0546] Step 2. Synthesis of Isocyanates from Carboxylic Acids

[0547] To 1 mmol of trans-4-methylcyclohexanecarboxylic acid dissolvedin 5 ml of DCM was added 1 mmol of triethyl amine and 1 mmol ofdiphenylphosphorazidate. The reaction was then stirred under nitrogenfor 30 minutes at 0° C. and then at 50° C. for 3 hours. The reaction wasthen cooled to room temperature, concentrated in vacuo, and then dry THFwas added to make up a stock solution of the isocyanate which was usedwithout further purification.

[0548] Step 3. Synthesis of Carbodiimide

[0549] To resin bound phophinimine (1 mmol) suspended in dry THF, wasadded 1 mmol of the isocyanate from step 2 above. The suspension wasthen stirred for 8 hours at 70° C. in a capped vial.

[0550] Step 4. Synthesis of Guanidine

[0551] The reaction product of step 3 above was cooled to roomtemperature and 1.2 equivalents of (2S,6S)-2,6-dimethylpiperazine(synthesized as in E. Jon Jacobson et al., J. Org. Chem., 60, 4177-83(1995)) were added. The reaction mixture was heated at 70° C. withstirring for 2 hours and cooled. The resulting mixture was filtered,washed with THF, and the combined filtrate was concentrated in vacuo andthe residue purified by silica gel chromatography, eluting with 10%methanol in DCM with 2% triethyl amine. The final product could befurther purified with reversed phase HPLC.

[0552] HPLC: 8.21 minutes

[0553] MS: MH+=544.5

Example 60 Synthesis of (acetyloxy)methyl(2S)-4-((E)-{[4-({[2-(2,4-dichlorophenyl)ethyl]amino}carbonyl)phenyl]amino}{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)-2-methylpiperazine-1-carboxylate

[0554] The synthesis of the above-named compound was accomplished byacylating the product prepared in Example 54 using the conditions setforth in J. Alexander et al. J. Med. Chem., 31, 318-322 (1988).

Examples 61-113

[0555] Examples 61-113 in the table below were synthesized in a mannersimilar to the above-described procedures (e.g. Example 8) or accordingto the following general procedures.

General Synthesis of Carboxamides

[0556] To a solution of an amine (1.0 equivalent) and 4-azidobenzoicacid (1.0 equivalent) or 4-nitrobenzoic acid (1.0 equivalent) in THF wasadded EDCl (1.5 equivalent), and the mixture was stirred at roomtemperature (8-12 hours). THF was removed and the residue wasresuspended in ethyl acetate, washed with water, dried with sodiumsulfate, concentrated, and purified by silica gel chromatography elutingwith ethyl acetate/hexane or chloroform/methanol.

General Synthesis of Guanidines

[0557] A. From Azidocarboxamides

[0558] To a solution of the corresponding azido carboxamide (1.0equivalent) in THF was added triphenylphosphine (1.0 equivalent) at roomtemperature. After 8 hours, the corresponding isocyanate was added (1.3equivalents) and the solution was heated at 55-80° C. overnight. To themixture was added an amine (1.3 equivalents). After being heated at thesame temperature for 2 hours, THF was removed. The residue wasresuspended in ethyl acetate, washed with water, dried over anhydroussodium sulfate, concentrated, and purified by silica gelchromatography(CHCl₃/MeOH 90:10+0.1% Et₃N 2% Et₃N). The final productscould be further purified with reversed phase HPLC.

[0559] B. From Nitrocarboxamides

[0560] The nitrocarboxamide was taken up in ethanol (or methanol) andpurged with dry nitrogen. To this solution was introduced activated Pd/C(10% w/w, 0.1 equivalent) and the mixture was hydrogenated for about 30minutes or until complete by LC/MS. The mixture was then filteredthrough Celite, concentrated in vacuo, and taken on crude to the nextstep.

[0561] To a 0.5 M acetone solution (0° C. ice bath) containing the amine(1 equivalent) and sodium carbonate (3 equivalents) was addedthiophosgene (3 equivalents) dropwise. After two hours at roomtemperature, the reaction mixture was concentrated in vacuo to removesolvent and excess thiophosgene. The residue was taken up in ethylacetate and washed with water, dried with sodium sulfate, and thenconcentrated in vacuo to yield the isothiocyanate. To a solution of theresulting isothiocyanate in dry THF (0.5 M solution) was added an amine(1.5 equivalents). After stirring overnight, the reaction mixture wasconcentrated in vacuo and the thiourea product was dissolved in ethylacetate or DCM and purified via flash chromatography.

[0562] To a solution of the thiourea in dry THF (0.1 M) was added EDC(2equivalents) and the solution was heated at reflux (˜80° C. externaltemp.) for 60 minutes, after which it was cooled to room temperature andthen placed in an ice bath for 15 minutes with stirring. A DCM solutioncontaining an amine (2 equivalents) was added and the reaction wasstirred at room temperature. After 20 minutes, the reaction was dilutedwith ethyl acetate and washed with water. The aqueous layer was backextracted with ethyl acetate and the combined organic layers, afterconcentration in vacuo, was purified by silica gel flash chromatography(typically eluting first with 10% MeOH in DCM followed by an addition of2% triethyl amine to the mobile phase) and/or reverse phase prep-HPLC.

Starting Materials and Intermediates

[0563] The requisite starting materials and intermediates correspondingto the examples in the tables are commercially available or may besynthesized by methods familiar to one of skill in the art, byprocedures shown in the preceding examples, or by the followingprocedures.

Preparation of Non-commercial Phenylethylamines

[0564] Phenyethyl amines used in the synthesis of Examples 83, 87 and 88may be prepared as described in J. Weinstock et al., J. Med. Chem.1166-1176 (1987), replacing nitromethane respectively with nitroethane,nitropropane and nitrobutane.

Preparation of [2S or R]-2-amino-3-[2,4dichlorophenyl]propan-1-ol

[0565] Prepared from L or D 2,4 dichlorphenylalanine following theprocedure as given in J. Org. Chem., 65, No. 16, pp 503 (2000).

Preparation of 6-chloro-3,4-dihydro-1H-naphthalen-2-one

[0566] Prepared according to Journal of Amer. Chem. Soc., 119,12722-12726 (1997) and Org Synthesis, 51, pp 109 (1971).

Preparation of 6-chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamine

[0567] Aza [6-chloro (2-1,2,3,4-tetrahydronaphthyl)]diazo methane may beprepared according to J. Org. Chem., 60, 4324-4330 (1995) (following theprescribed procedure except that the mesylate intermediate was convertedto azide without purification on silica gel column). Aza [6-chloro(2-1,2,3,4-tetrahydronaphthyl)]diazo methane (1.0 equivalent) was thendissolved in THF to which triphenylphosphine (1.0 equivalent) was addedand reaction mixture allowed to stir at 70° C. for 1 hour. Thereafter,5% KOH was poured and further THF was added to make one phase and thesolution was stirred for another 1 hour at 70° C. All the THF wasremoved and the KOH layer was extracted with CHCl₃ (3×). Combinedorganic extracts were washed with 1N HCl (2×) and organic phase wasdiscarded. The aqueous layer was further treated with 5% KOH (5 ml) andamine so formed was extracted in CHCl₃ washes (3×). CHCl₃ extracts werefurther washed with brine and dried over Na₂SO₄. The removal of solventin vacuo gave the pure amine.

Preparation of 6-fluoro-3,4-dihydro-1H-naphthalen-2-one

[0568] 4-fluorophenylacetic acid (1 equivalent) was dissolved indichloroethane (1.3 M) containing SOCl₂ (3 equivalents), the mixture wasrefluxed for 90 minutes and the solvent was removed. Solution of thiscrude product in CH₂Cl₂ was added dropwise within 60 minutes to AICl₃ (2eq) in CH₂Cl₂ (0.4 M) while stirring at 0° C. Thereafter, ethylene wasintroduced at 0° C. over 45 minutes, whereupon the mixture was stirredfurther at room temperature for 1 hour, and thereafter was treated at 0°C. with ice-water. The organic phase was washed with 1N HCl (2×), NaHCO₃(sat. sol.), dried and evaporated. The residue was triturated withhexane, yielding the product as a bright yellow solid.

Preparation of 6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine

[0569] Over a solution of 6-fluorotetralone (6-fluoro-3,4-dihydro-1H-naphthalen-2-one; 1 equivalent) and ammonium acetate (5 equivalents)in a 2:1 mixture of MeOH:THF (0.24 M), was carefully added NaCNBH₃ (2eq), and the reaction mixture was stirred at room temperature for 2hours. Concentrated HCl was added at 0° C. until the pH was less than 2,and the MeOH was removed in vacuo. The residue was taken up in water andextracted with CHCl₃ (2×). The aqueous solution was basified with solidKOH and extracted with CHCl₃ (3×). The combined extracts were dried(MgSO₄) and evaporated in vacuo to give the titled compound.

Preparation of 2-(4-bromo-2-fluoro) Nitrostyrene

[0570] 4-Bromo-2-fluorobenzaldehyde 1 (1 equivalent) was dissolved inanhydrous methanol (0.3 M) and nitromethane (1 equivalent) was added andthe reaction was chilled in ice. Excess DBU (11.04 mL, 73.8 mmol) wasadded dropwise to the reaction and stirring continued at 0° C. for 25minutes. The reaction was then poured into 180 mL of 3 M HCl (22equivalents). A solid precipitated out and was collected by filtration.The yellow solid was redissolved in ether and dried over Na₂SO₄,filtered and concentrated to afford 2-(4-bromo-2-fluoro)nitrostyrene asa yellow solid. MS: 247.9 (M+H).

Preparation of 2-(4-bromo-2-fluorophenyl)ethylamine

[0571] 4-Bromo-2-fluoronitro styrene (1 equivalent) in THF (0.2 M) wascooled to 0° C. and treated with 1.0 M BH₃ in THF (5 equivalents). Thereaction was heated to reflux overnight. The reaction was cooled to 0°C. and quenched with H₂O then 1 N HCl until a pH of about 2 wasachieved. The reaction was stirred for 30 minutes at room temperatureand then extracted with ether (3×). The aqueous layer was made basicwith 5% NaOH solution. The aqueous layer was then extracted into ether(3×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated to give crude2-(4-bromo-2-fluorophenyl)ethylamine. Purification by flashchromatography eluting with 2%-5%-10% MeOH/CH₂Cl₂ gradients containing1% concentrated ammonia afforded the desired compound. MS m/z 219.8(M+H).

Preparation of6-azido-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide

[0572] 6-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide (1equivalent) and sodium azide (2.6 equivalents) were suspended inanhydrous DMSO (0.6 M) under nitrogen. The mixture was heated at 100° C.for four days. Ethyl acetate was added and the organic phase washed withwater and brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was evaporated to dryness and the resultant residue dissolvedin a 1:1 ethyl acetate/DCM mixture. This solution was purified by flashchromatography over silica (1:1 ethyl acetate/DCM). The fractionscoeluting with the major band (Rf 0.53, eluent: 1:1 ethyl acetate/DCM)were combined and evaporated to dryness. The residue was recrystallizedfrom acetonitrile to give6-azido-N-[2-(2,4-dichlorophenyl)ethyl]-pyridine-3-carboxamide as paleyellow needles. LCMS (MH+) 336.

Preparation of 4-Azido-N-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-benzamide

[0573] Step 1.

[0574] 2-Fluoro-4-methoxy-benzaldehyde (1 equivalent) was dissolved inMeOH and chilled in an ice bath. Nitromethane (1 equivalent) was added.NaOH (1.05 equivalents) in water was added dropwise to thenitromethane/aldehyde solution, such that the temperature did not riseabove 15° C. The reaction was then allowed to stir at 0° C. for 15minutes. The reaction mixture was poured into concentrated HCl dilutedwith water. Product was extracted with EtOAc and washed with water,brine, and dried (Na₂SO₄). Solvent was removed to yield a yellow oilwhich was freeze-dried in 90% MeCN/H₂O to give the product2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene, which was used withoutfurther purification.

[0575] Step 2.

[0576] LiAIH₄ (3.5 equivalents) was suspended in THF and brought toreflux. 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene (1 equivalent) wasdissolved in THF and added dropwise to the LiAIH₄. The reaction wasallowed to proceed at reflux overnight. The reaction was then cooled inan ice bath and H₂SO₄ was added dropwise. The reaction was extractedwith ether. The ether fractions were discarded. The aqueous layer wasadjusted to pH 12 with 5% NaOH and extracted with ether (3×). Combinedether fractions were washed with brine and dried over Na₂SO₄. Solventwas removed to yield 2-(2-fluoro-4-methoxy-phenyl)-ethylamine as an oil,which was used without further purification.

[0577] Step 30

[0578] 4-Azidobenzoic acid (1.5 equivalents) was dissolved in THF. EDC(1.5 equivalents), DIEA (1.5 equivalents) and DMAP (0.1 equivalents)were added followed by 2-(2-fluoro-4-methoxy-phenyl)-ethylamine (1equivalent). The reaction was then allowed to stir overnight at roomtemperature. EtOAc was added and the reaction was washed with 10% citricacid, 10% sodium bicarbonate and brine. After drying over Na₂SO₄,solvent was removed and the residue was purified by flash chromatography20% EtOAc/DCM to yield the title compounds as a white powder.

Preparation of 7-Methoxy-2,3,4,5-tetrahydro-1 H-benzo[d]azepine

[0579] Step 1.

[0580] 2-(3-Methoxy-phenyl)-ethylamine (1 equivalent) was dissolved inanhydrous DCM (0.88 M) in a three necked round-bottomed flask under N₂and stirred in an ice bath. Tosyl chloride (1.25 equivalents) was thendissolved in anhydrous DCM under N₂ and added to the stirring solutionover 10 minutes (Caution! Exothermic reaction). A precipitate formed,DIEA (1.2 equivalents) was then added, and the reaction was stirred atroom temperature overnight. The reaction was then washed with 10% citricacid, 10% sodium carbonate, and brine before being dried over sodiumsulfate. The organic solvent was then removed under reduced pressure toleave a brown oil. This crude material was then purified via flashchromatography using 100% DCM running solvent to recover the productsulfonamide. (MH+) 306.1.

[0581] Step 2.

[0582] The Sulfonamide (1 equivalent) was dissolved in acetone andstirred in a round-bottomed flask with K₂CO₃ (6.9 equivalents). This waswarmed to 78° C. and refluxed, ethyl bromoacetate (1.5 equivalents) wasthen added, and the reaction was allowed to proceed overnight. The K₂CO₃was then filtered off and the solvent removed under reduced pressure. Tothis colorless oil was added NaOH (4.4 equivalents) dissolved in 50%EtOH (0.4 M) and then warmed to reflux at 90° C. and allowed to proceedovernight. The EtOH was then removed under reduced pressure. Theresidual oil was then washed with water and extracted with diethylether. The aqueous layer was then acidified with concentrated HCl andextracted with diethyl ether (2×). The organic layers were then combinedand extracted with sodium carbonate (2×). The aqueous layers were thencombined and acidified with concentrated HCl and extracted with diethylether (2×). The organic layers were then combined and dried over sodiumsulfate. The organic solvent was then removed under reduce pressure.This material was then recrystallized from ethyl acetate/petroleumspirit to recover the alkylated product[[2-(3-Methoxy-phenyl)-ethyl]-(toluene-4-sulfonyl)-amino]-acetic acid.(MH+) 363.9.

[0583] Step 3.

[0584] [[2-(3-Methoxy-phenyl)-ethyl]-(toluene-4-sulfonyl)-amino]-aceticacid (1 equivalent) was dissolved in anhydrous DCM (0.13 M) and added toa stirring solution of P₂O₅ (5 equivalents) suspended in anhydrous DCM(0.13 M) at 0° C. under nitrogen. This reaction was then allowed toproceed at room temperature for two days before being worked up. Thereaction mixture was then diluted with 3% NaOH and extracted with DCM.The organic layers were then combined and dried over sodium sulfate andthe solvent removed under reduced pressure to recover the cyclizedproduct8-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-one.Note the formation of the regio-isomer (ortho cyclized product). Thismaterial was then purified via flash chromatography using 20%acetone/petroleum spirit running solvent. Two separate fractions of thedesired isomeric pure8-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-onewere recovered. These two fractions were treated separately for the nextreaction. (MH+) 346.1.

[0585] Step 4.

[0586] The ketone product from step 3 was dissolved in neat TFA andstirred under nitrogen. To this stirring solution was addedtriethylsilane (2.2 equivalents) and the reaction allowed to proceedovernight at room temperature. Aqueous sodium carbonate was then addedand the solution extracted with ether (2×). The ether layers were thencombined and dried over sodium sulfate and the solvent removed underreduced pressure to recover an orange oil. The crude material from thetwo reactions were then combined and purified via flash chromatographyusing 20% acetone/1% ammonia solution/petroleum spirit to give7-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1 H-benzo[d]azepine.(MH+) 178.0.

[0587] Step 5.

[0588] Gaseous ammonia was first condensed into an oven-dried threenecked round-bottomed flask in a dry ice/acetone bath under N₂. Sodiummetal was then added to this vigorously stirring liquid ammonia to formsodium amide. Note the solution should hold a deep blue color to confirmthat the liquid ammonia is -anhydrous. The sulfonamide (1 equivalent)from step 4 was then dissolved in THF (0.1 M) in an oven-driedround-bottomed flask connected to a dry ice condenser. The anhydrousliquid ammonia was then distilled across into the round-bottomed flaskcontaining the sulfonamide with vigorous stirring via the dry icecondenser connected in a series under a steady stream of N₂. Once thedistillation had finished, the condenser and flask containing thesulfonamide was isolated. Sodium metal (2.1 equivalents) was then addeduntil the solution again went a deep blue color. The reaction wasstirred for a further 30 minutes before being quenched with NH₄Cl (9.3equivalents). The reaction was then extracted with diethyl ether anddried over sodium sulfate and the solvent removed under reduced pressureto give the product amine as a yellow oil. (MH+) 353.3.

Preparation of(4-Azido-phenyl)-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-methanone

[0589] 7-Methoxy-2,3,4,5-tetrahydro-1 H-benzo[d]azepine (1 equivalent)was dissolved in THF (0.1 M) along with azidobenzoic acid (1.5equivalents), EDC (1.5 equivalents), DMAP (0.18 equivalents), and DIEA(1.5 equivalents). The reaction was stirred at room temperatureovernight. The reaction was then washed with 10% citric acid, saturatedsodium carbonate, and brine. The organic layer was then dried oversodium sulfate and the organic solvent removed under reduced pressure.The material was then purified via flash chromatography using 8%acetone/1% ammonia solution/petroleum spirit running solvent to give thetitle compound. (MH+) 323.2.

Preparation of 5-Methoxy-2-indamine

[0590] Step 1.

[0591] A mixture of 4-methoxyphenylacetic acid (1 equivalent), freshlydistilled thionyl chloride (5.6 equivalents) and DMF was heated atreflux for 30 minutes. The mixture was allowed to cool and evaporated todryness to give an orange oil. The crude product was used for the nextstep without further purification. A diazomethane solution was cooled inan ice bath. A solution of the crude product from the previous step inether was added slowly. The flask was fitted with a calcium chloridedrying tube and allowed to stand at room temperature for 16 hours. Themixture was evaporated to dryness by bubbling nitrogen through thereaction mixture with external heating at 30° C. The residue waspurified by flash chromatography over silica (DCM, 5% ethylacetate/DCM). The fractions coeluting with the major band were combinedand evaporated to dryness to give1-diazo-3-(4-methoxyphenyl)propan-2-one as an orange oil. (MH+) 191.

[0592] Step 2.

[0593] A solution of 1-diazo-3-(4-methoxyphenyl)propan-2-one (1equivalent) in anhydrous DCM (0.1 M) was prepared under nitrogen. Asuspension of rhodium (II) acetate dimer (0.02 equivalents) in anhydrousDCM (0.01 M) was prepared under nitrogen. The diazoketone solution wastransferred to the rhodium acetate dimer suspension via cannula and themixture stirred at room temperature for 90 minutes. The mixture wasfiltered (Whatmann No 1 filter paper) and the filtrate evaporated todryness. The residue was purified by flash chromatography over silica(eluent DCM). The fractions coeluting with the major non-polar band (Rf0.62) were combined and evaporated to dryness to give5-methoxy-2-indanone as a yellow solid. (MH+) 162.

[0594] Step 3.

[0595] A mixture of 5-methoxy-2-indanone (1 equivalent) and methoxyaminehydrochloride (2.5 equivalents) was dissolved in a 1:1 mixture (0.24 M)of ethanol and pyridine. The mixture was heated at reflux for 30 minutesand allowed to cool. Water was added and the mixture was extracted withethyl acetate. The ethyl acetate extracts were dried over anhydroussodium sulfate and filtered. The filtrate was evaporated to dryness togive an orange oil which was used for the next step without furtherpurification. The crude product from the previous step was dissolved inanhydrous THF under N₂. A borane-THF complex solution (1.0M, 4.7equivalents) was added and the mixture heated at reflux under N₂ for 3hours. Methanol was added and the mixture evaporated to dryness. HCl(3M, 24 equivalents) was added to the residue and the mixture heated at90° C. for 1 hour. NaOH solution (10M, 25 equivalents) was added and theaqueous phase extracted with ethyl acetate (3×). The combined ethylacetate extracts were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness and the residue purified by flashchromatography over silica (eluent 10% methanol, 1% concentrated ammoniasolution in DCM). The fractions coeluting with the major band (Rf 0.31,eluent: 10% methanol, 1% concentrated ammonia solution in DCM, bandsvisualized by spraying with Ninhydrin and heating) were combined andevaporated to dryness to give 5-methoxy-2-indamine as a pale brown oil.(MH+) 164.2.

[0596] Table of Examples 61-113 Example Name MH+ 614-{[(Z)-(cyclopentylimino)(piperazin-1- 488 yl)methyl]amino}-N-[2-(2,4-dichlorophenyl)ethyl]benzamide 624-{[(Z)-(cyclopentylimino)(1,4-diazepan- 5021-yl)methyl]amino}-N-[2-(2,4- dichlorophenyl)ethyl]benzamide 63N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 530.5[(3-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 64 N-[2-(2,4-dichlorophenyl)ethyl]-4-{[(E)-544.5 [(3S)-3-methylpiperazin-1- yl](tricyclo[3.3.1.1˜3,7˜]dec-2-ylimino)methyl]amino}benzamide 65N-[2-(2,4-dichlorophenyl)ethyl]-4-[((Z)- 584.4[(3S)-3-methylpiperazin-1-yl]{[4-(trifluoromethyl)cyclohexyl]imino}methyl) amino]benzamide 66N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 558[(3S)-3-methylpiperazin-1-yl][(2- propylcyclohexyl)imino]methyl}amino)benzamide 67 N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 572.3[(3R,5S)-3,5-dimethylpiperazin-1-yl][(2-propylcyclohexyl)imino]methyl}amino)be nzamide 68N-[2-(2,4-dichlorophenyl)ethyl]-4-{[(E)- 568 [(3S)-3-methylpiperazin-1-yl](tricyclo[3.3.1.1˜3,7˜]dec-2- ylimino)methyl]amino}benzamide 69N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 584.3[(3R,5S)-3,5-dimethylpiperazin-1-yl][(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)imino]methyl}amino)benzamide 70N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 570.3[(3S)-3-methylpiperazin-1-yl][(1,1,7- trimethylbicyclo[2.2.1]hept-2-yl)imino]methyl}amino)benzamide 71N-[2-(2,4-difluorophenyl)ethyl]-4-({(E)- 498.2[(4-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 72 N-[2-(2,4-dichlorophenyl)ethyl]-4-[((E)-570.1 [(3S)-3-methylpiperazin-1- yl]{[(1S,2R,3S,6R)-3,7,7-trimethylbicyclo[4.1.0]hept-2- yl]imino}methyl)amino]benzamide 73N-[2-(2,4-dichlorophenyl)ethyl]-4-({(Z)- 558.2[(3R,5S)-3,5-dimethylpiperazin-1-yl][(4-ethylcyclohexyl)imino]methyl}amino)ben zamide 746-({(Z)-(cyclohexylimino)[(3S)-3- 517methylpiperazin-1-yl]methyl}amino)-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3- carboxamide 75N-[2-(2,4-dichlorophenyl)ethyl]-4-({(E)- 544.2[(4-ethylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 76 4-({(Z)-(cyclohexylimino)[(3S)-3- 530.2methylpiperazin-1-yl]methyl}amino)-N-[2- (2,4-dichlorophenyl)-1-methylethyl]benzamide 77 N-{2-[2,4-bis(methyloxy)phenyl]ethyl}-4- 522.4({(Z)-[(4-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 78 N-[2-(2,4-dichlorophenyl)-1-methylethyl]-544.2 4-({(Z)-[(4-methylcyclohexyl)imino][(3S)- 3-methylpiperazin-1-yl]methyl}amino)benzamide 79 N-[2-(2,4-dichlorophenyl)ethyl]-4-{[(Z)-636.2 [(3R,5S)-3,5-dimethylpiperazin-1- yl]({(1S,2S)-2-[(phenylmethyl)oxy]cyclohexyl}imino)met hyl]amino}benzamide 80N-[2-(2,4-dichlorophenyl)ethyl]-6-({(E)- 531.2[(4-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)pyridine-3-carboxamide 814-({(Z)-(cyclohexylimino)[(3S)-3- 476methylpiperazin-1-yl]methyl}amino)-N-[2-(2,4-dimethylphenyl)ethyl]benzamide 82N-{2-[2,4-bis(methyloxy)phenyl]ethyl}-4- 562.2[((Z)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 83N-[2-(2,4-dichlorophenyl)-1-methylethyl]- 584.24-[((Z)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 84N-[2-(2,4-dimethylphenyl)ethyl]-4-[((E)- 530 [(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]benzamide 85N-[2-(2,4-dimethylphenyl)ethyl]-4-[((E)- 544 (3,5-dimethylpiperazin-1-yl){[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]benzamide 86N-[2-(2,4-dichlorophenyl)ethyl]-6-[((E)- 571.2[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]pyridine-3-carboxamide 87 N-{1-[(2,4-dichlorophenyl)methyl]propyl}- 598.24-[((Z)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 88N-{1-[(2,4-dichlorophenyl)methyl]butyl}- 612.24-[((Z)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 894-[((Z)-[(3S)-3-methylpiperazin-1- 516.3 yl]{[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]-N-[(2S)-2-phenylpropyl]benzamide 90 4-[((Z)-[(3S)-3-methylpiperazin-1- 516.3yl]{[(1S,2S,3R,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]-N-[(2R)-2- phenylpropyl]benzamide 91N-[2-(2,4-dichlorophenyl)ethyl]-4-[((E)- 584.7 (3,5-dimethylpiperazin-1-yl){[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]benzamide 92N-[2-(2,4-difluorophenyl)ethyl]-4-[((E)- 538.2[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 93N-[2-(2,4-dichlorophenyl)ethyl]-4-{[(E)- 598.7 {[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}(3,4,5-trimethylpiperazin-1-yl)methyl]amino}benzamide 94 N-{2-[2-fluoro-4- 550.2(methyloxy)phenyl]ethyl}-4-[((Z)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 95N-[(1S)-2-(2,4-dichlorophenyl)-1- 600.4(hydroxymethyl)ethyl]-4-[((E)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 96N-[(1R)-2-(2,4-dichlorophenyl)-1- 600.5(hydroxymethyl)ethyl]-4-[((E)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 97N-(6-chloro-1,2,3,4- 562.3 tetrahydronaphthalen-2-yl)-4-[((Z)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 98N-[2-(2-fluoro-4-methylphenyl)ethyl]-4- 494.6({(E)-[(4-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 99 N-[2-(2,4-dichlorophenyl)ethyl]-N-methyl-584.7 4-[((E)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 100N-[2-(2,4-dichlorophenyl)ethyl]-2-fluoro- 588.64-[((E)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 701N-(6-fluoro-1,2,3,4- 546 tetrahydronaphthalen-2-yl)-4-[((E)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 102N-[6-(methyloxy)-1,2,3,4- 558 tetrahydronaphthalen-2-yl]-4-[((Z)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 103N-{2-[2-fluoro-4- 524.2 (methyloxy)phenyl]ethyl}-4-({(Z)- {[(1S,2S)-2-methylcycloheptyl]imino}[(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 104 N-[2-(4-bromo-2-fluorophenyl)ethyl]-4- 598[((E)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 105N-{2-[4-fluoro-2- 588 (trifluoromethyl)phenyl]ethyl}-4-[((E)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 106N-[2-(4-bromo-2-fluorophenyl)-2- 614 hydroxyethyl]-4-[((E)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 107N-[2-(2-fluoro-4-methylphenyl)ethyl]-4- 508.3 ({(Z)-{[(1S,2S)-2-methylcycloheptyl]imino}[(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 108 N-[2-(4-bromo-2-fluorophenyl)ethyl]-4-612.2 [((Z)-[(3S)-3-methylpiperazin-1-yl]{[4-(trifluoromethyl)cyclohexyl]imino}methyl) amino]benzamide 109N-[5-(methyloxy)-2,3-dihydro-1H-inden- 544.32-yl]-4-[((Z)-[(3S)-3-methylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 1104-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 564.3yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]-N-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}benzamide 111N-[2-(4-bromo-2-fluorophenyl)ethyl]-4- 612[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzamide 112N-[2-(4-bromo-2-fluorophenyl)ethyl]-4- 558({(Z)-[(4-methylcyclohexyl)imino][(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide 113 N-[2-(4-bromo-2-fluorophenyl)ethyl]-4- 558({(Z)-(cycloheptylimino)[(3S)-3- methylpiperazin-1-yl]methyl}amino)benzamide

Examples 114-118

[0597] Examples 114-118 listed in the following Table were preparedusing the general procedures described above.

[0598] Table of Examples 114-118 Example Name MH+ 1144-[((1E)-[(3S)-3-methylpiperazin-1- 528.3 yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]amino}methylidene)amino]-N-[(2R)-1,2,3,4-tetrahydronaphthalen- 2-yl]benzamide 115N-[(2R)-5-(methyloxy)-1,2,3,4- 558.7tetrahydronaphthalen-2-yl]-4-[((1E)- [(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]amino}methylidene)amino]benza mide 116 N-[(2S)-7-(methyloxy)-1,2,3,4-558.8 tetrahydronaphthalen-2-yl]-4-[((1E)- [(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]amino}methylidene)amino]benza mide 1174-({(1E)-(cycloheptylamino)[(3S)-3- 488.6 methylpiperazin-1-yl]methylidene}amino)-N-[(2R)- 1,2,3,4-tetrahydronaphthalen-2-yl]benzamide 118 N-[(2S)-5-(methyloxy)-1,2,3,4- 558.7tetrahydronaphthalen-2-yl]-4-[((1E)- [(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]amino}methylidene)amino]benza mide

Example 119

[0599] EC₅₀ values of test compounds were determined by treating cellsexpressing MC4-R with test compound and lysing the cells and measuringintercellular cAMP concentration with Amersham-Pharmacia RPA-559 cAMPScintillation Proximity Assay (SPA) kit. The following compounds weresynthesized and tested according to this assay. The compounds listedbelow displayed −log EC₅₀ values above about 3. The title compounds ofExamples 61-118 also all displayed −log EC₅₀ values above about 3. Forthis reason each of the compound in the following list and each of thetitle compounds of Examples 61-118 are individually preferred and arepreferred as a group. Furthermore, the groups corresponding to R¹through R¹⁰ for each of these compounds are also preferred. Nomenclaturefor these compounds was provided using Nomenclator (v.3.0 & v.5.0) fromCmemlnovation Software, Inc. The following compounds are merelyillustrative and should not be construed as limiting of the instantinvention:

[0600]{4-[((1Z)-2-aza-2-cyclopentyl-1-piperazinylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((5S)-2,5-dimethylpiperazinyl)(1Z)-2--aza-3-methylbut-1-enyl]amino}phenyl)-N-[2,-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-2-cyclohexyl-1-(3-oxopiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cyclohexyl-1-morpholin-4-ylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cyclohexyl-1-piperazinylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclopentylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cyclopentyl-1-(1,4-diazaperhydroepinyl)vinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1Z)-1-[(2-amino-2-methylpropyl)amino]-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-(2,5-diazabicyclo[2.2.1]hept-2-yl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-oxocyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-2-cyclohexyl-1-(3-hydroxypiperidyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-2-chlorophenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cyclohexyl-1-(1,4-diazaperhydroepinyl)vinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3R)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[((1Z)-2-aza-2-cyclohexyl-1-piperazinylvinyl)amino]methyl}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclopentylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(2,5-dimethylpiperazinyl)-2-cyclopentylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cycloheptyl-1-piperazinylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-difluorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(4-chlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(4-fluorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-(2-phenylethyl)carboxamide,(4-{[(1E)-2-aza-2-(2,4-dichlorophenyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-2-cyclohexyl-1-(3-imino-1-oxo(2,5,6,7,8,8a-hexahydro-2,7-diazaindolizin-7-yl))vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-[4-(trifluoromethyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohex-3-enylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-2-cyclohexyl-1-(4-methylpiperidyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-5-chloro-2-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1E)-1-[(3-aminocyclohexyl)amino]-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((5S)-2,5-dimethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-3-methylphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}methyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[((1Z)-2-aza-2-cyclohexyl-1-(1,4-diazaperhydroepinyl)vinyl)amino]methyl}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1E)-1-[((1S,2R)-2-aminocyclohexyl)amino]-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-ethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(2-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3,4-dimethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,3-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3R,5R)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(3-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(2,6-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-((1R,2R)-2-methylcyclohexyl)-1-((3S)-3-methylpiperazinyl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}-3-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(4-chlorophenyl)ethyl]carboxamide,[4-({(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-[4-(trifluoromethyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,6-diazabicyclo[4.3.0]non-3-yl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-(3,5-dimethylpiperazinyl)(1Z)-2-aza-2-bicyclo[2.2.1]hept-2-ylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperidyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}-5-chloro-2-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-cyclohexylvinyl]amino}phenyl)-N-(2-indol-2-ylethyl)carboxamide,[4-({[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}methyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({[(1Z)-2-aza-1-(2,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}methyl)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S,5R)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-cycloheptylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({1-[(3S)-3-(methylethyl)piperazinyl](1Z)-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-3-cyclohexylprop-1-enyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S,5R)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-(3-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S,5R)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-((2S,1R)-2-methylcyclohexyl)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-((1R,2R)-2-methylcyclohexyl)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-((1R,2R)-2-methylcycloheptyl)-1-((3S)-3-methylpiperazinyl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(2,2-dimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S,5S)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-(4-methylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({1-[(3S)-3-(2-methylthioethyl)piperazinyl](1Z)-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}-3-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(4-methoxycyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1E)-2-aza-1-{[2-(diethylamino)ethyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-indan-2-ylvinyl]amino}phenyl)-N-[2-(4-fluorophenyl)ethyl]carboxamide,[4-({(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-[2-(methylethyl)phenyl]vinyl}amino)phenyl]-N-[2-(4-chlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-3-methylbut-1-enyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1E)-2-aza-1-[({5-[(dimethylamino)methyl](2-furyl)}methyl)amino]-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(2,5-diazabicyclo[4.4.0]dec-2-yl)-2-cyclohexylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-cyclohexylvinyl]amino}phenyl)-N-(2-indol-3-ylethyl)carboxamide,[4-({(1E)-2-aza-2-[4-(tert-butyl)cyclohexyl]-1-piperazinylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({1-[(3S)-3-(2-methylpropyl)piperazinyl](1Z)-2-aza-2-cyclohexylvinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(3,3,5-trimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[1-((3S,5R)-3,5-dimethylpiperazinyl)(1Z)-2-aza-2-cyclooctylvinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-2-(2,6-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-2-(2,3-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-((1R,2R)-2-methylcycloheptyl)-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1 E)-2-((1R,2R)-2-ethylcyclohexyl)-1-((3S,5R)-3,5-dimethylpiperazinyl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-2-(2,2-dimethylcyclohexyl)-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(2-propylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(1,2,3,4-tetrahydronaphthyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1Z)-2-aza-2-cyclohexyl-1-[4-(2-furylcarbonyl)piperazinyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}hex-1-enyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-methylphenyl)methyl]amino}-3-methylbut-1-enyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-adamantan-2-yl-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-[2-(methylethyl)phenyl]vinyl}amino)phenyl]-N-[2-(4-methoxyphenyl)ethyl]carboxamide,(4-{[(1E)-2-((1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-1-((3S)-3-methylpiperazinyl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-((1S,5S,2R,3R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-2-azavinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-(2-thienyl)ethyl)carboxamide,[4-({(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-[4-(tert-butyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S,5R)-3,5-dimethylpiperazinyl)-2-aza-2-(3,3,5-trimethylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-1-((3S,5R)-3,5-dimethylpiperazinyl)-2-aza-2-(2-propylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-2-cyclohexyl-1-(3-phenylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(1,2,3,4-tetrahydronaphthyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1Z)-2-aza-1-(3,5-dimethylpiperazinyl)-2-indan-2-ylvinyl]amino}phenyl)-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-ethylphenyl)methyl]amino}-3-methylbut-1-enyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,(4-{[(1E)-2-adamantan-2-yl-2-aza-1-(3,5-dimethylpiperazinyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{6-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino](3-pyridyl)}-N-(2-phenylethyl)carboxamide,(4-{[(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1E)-1-(3,5-dimethylpiperazinyl)-2-aza-2-[4-(tert-butyl)cyclohexyl]vinyl}amino)phenyl]-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,[4-({(1Z)-2-aza-2-cyclohexyl-1-[(imidazol-2-ylmethyl)benzylamino]vinyl}amino)phenyl]-N-(2-phenylethyl)carboxamide,(4-{[(1E)-1-((3S)-3-methylpiperazinyl)-2-aza-2-(4-phenylcyclohexyl)vinyl]aminophenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-bromophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(3-chlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-chlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-chlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-fluorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2-fluorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-phenylethyl)carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-hydroxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-cyclohex-1-enylethyl)carboxamide,(4-{[(1E)-2-aza-1-(3,5-dimethylpiperazinyl)-2-(4-phenylcyclohexyl)vinyl]amino}phenyl)-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-methylphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[(2,4-dichlorophenyl)methyl][2-(dimethylamino)ethyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-chlorophenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(2-chlorophenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(3-chlorophenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-methyl-N-(2-phenylethyl)carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methylphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(3-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-1-hydroxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-2-cyclohexyl-1-{[(4-fluorophenyl)methyl](2-pyridylmethyl)amino}vinyl)amino]phenyl}-N-(2-phenylethyl)carboxamide,[4-({(1E)-2-aza-1-[({1-[(4-chlorophenyl)methyl]-5-methylimidazol-4-yl}methyl)amino]-2-cyclohexylvinyl}amino)phenyl]-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-ethylphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1E)-2-aza-2-cyclohexyl-1-{[1-benzyl(4-piperidyl)]amino}vinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,3-{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-phenylethyl)propanamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,4-dichlorophenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(3-methylphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(2,5-dimethoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-methoxyphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(3-methoxyphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl][(4-ethylphenyl)methyl]amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl](4-quinolylmethyl)amino}-2-cyclohexylvinyl)amino]phenyl}-N-[2-(4-methoxyphenyl)ethyl]carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2,2-diphenylethyl)carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2,2-diphenylethyl)carboxamide,{4-[((1Z)-2-aza-1-{[2-(dimethylamino)ethyl]benzylamino}-2-cyclohexylvinyl)amino]phenyl}-N-(2-phenylethyl)-N-benzylcarboxamide,and (acetyloxy)methyl(2S)-4-((E)-{[4-({[2-(2,4-dichlorophenyl)ethyl]amino}carbonyl)phenyl]amino}{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)-2-methylpiperazine-1-carboxylate.

Example 120 In Vivo Studies of MC4-R Agonists on Energy Intake, BodyWeight, Hyperinsulinemia, and Glucose Levels

[0601] In vivo studies were conducted to observe the effect of MCR-4agonists on energy intake, body weight, hyperinsulinemia, and glucoselevels. All studies were conducted with male 9-10 week old ob/ob micewhich display early onset of obesity, insulin resistance and diabetesdue to leptin deficiency. Mice were acclimated in the facility for 1week before studies and are caged individually. Vehicle-treated(control) and drug treated mice studies were always run in parallel. Inmulti-day studies, mice (8-15 per group) were monitored for baselinebody weight, fasting levels of glucose, insulin, blood lipids and energyexpenditure and then injected twice daily (9 a.m. and 5 p.m.) with 3mg/kg of the MC4-R agonist4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks. Body weight as well as food and water intake were monitoreddaily. Animals were fasted overnight for measurements of fasting levelsof glucose, insulin, and lipids once a week until the end of the study.Energy expenditure (resting metabolic rate, i.e., O2 consumption and CO2production) were monitored in air tight chambers at the end of the studyon fed animals. O₂ consumption and CO₂ production were measured usingOxymax systems (Columbus Instruments). Oral glucose tolerance test(OGTT—a routine test for diabetes and glucose intolerance) was performedon overnight fasted mice at the end of the study. Blood glucose and oralglucose tolerance were measured using a glucose monitor (Onetouch soldby Lifescan). Free fatty acids were measured using an non-esterifiedfree fatty acids enzymatic assay (Waco Chemicals). Serum Insulin levelswere measured by immunoassay (Alpco).

Results

[0602] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon food intake is shown in FIG. 1. FIG. 1 shows total food intake asrepresented as grams/mouse/day throughout the 4 week study. Food ismonitored every morning. Cumulative food intake represents the totalamount of grams the mice consumed during the study. Each group (vehicleor drug) had 15 mice. As shown in FIG. 1, a significant reduction infood intake was demonstrated in those mice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0603] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon body weight is shown in FIG. 2. FIG. 2 shows body weight reduction asrepresented as grams/mouse throughout the 4 weeks of the study. Micewere weighed every morning. At the end of the study, drug treated miceweighed 19% less than the vehicle treated mice. Each group (vehicle ordrug) had 15 mice. As shown in FIG. 2, significant body weight reductionwas demonstrated in those mice treated IP with 4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0604] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon blood glucose levels in shown in FIG. 3. FIG. 3 shows blood glucoselevels as represented as mg of glucose/di of blood. Mice were fastedovernight and glucose levels were measured at 8 a.m. the followingmorning. Vehicle treated mice showed an increase in blood glucoseconsistent with the rapid progression of diabetes in this mouse strainwhereas, diabetes was slowed down considerably (47% decrease) in drugtreated mice. Each group (vehicle or drug) had 8 mice. As shown in FIG.3, a significant reduction in fasting glucose levels were demonstratedin those mice treated IP with4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamidefor 4 weeks.

[0605] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon glucose levels during oral glucose tolerance test (OGTT) is shown inFIG. 4. FIG. 4 shows OGTT as performed on overnight fasted mice at theend of the study. Blood glucose is represented as mg of glucose/dl ofblood. Glucose levels were measured the following morning: 90 minutesbefore and 25, 60 and 120 minutes after an oral glucose load (2 mg/kg).Orally administered glucose quickly elevated blood glucose, similar to ameal, and the response to this exogenous glucose gave a measure of howwell the body regulated glucose horneostasis. As shown in FIG. 4,vehicle treated mice showed an elevated response to glucose consistentwith their diabetic state, whereas drug treated mice showed a very muchimproved glucose disposal, illustrated as a 45% decrease of the areaunder the curve. Each group (vehicle or drug) had 15 mice.

[0606] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon free fatty acid (FFA) levels is shown in FIG. 5. FIG. 5 shows FFArepresented as mmoles of FFA/L of serum. Mice were fasted overnight andfree fatty acid levels were measured at 8 a.m. the following morning. Asshown in FIG. 5, vehicle treated mice showed elevated levels of FFAthroughout the study consistent with their obese state, whereas the drugtreated mice diabetes showed a dramatic 50% decrease. Each group(vehicle or drug) had 8 mice.

[0607] The effect of4-[(N-cyclohexyl-3,5-dimethyl-piperazine-1-carboximidoyl)-amino]-N-[2-(2,4-dichlorophenyl)-ethyl]-benzamideon serum insulin levels is shown in FIG. 6. Serum insulin levels weremeasured one hour after single IP dosing of 1 and 3 mg/kg in overnightfasted ob/ob mice. In FIG. 6, serum insulin levels are represented as ngof insulin/ml of serum. As shown in FIG. 6, drug treated mice showed adose dependent decrease of 27% and 55% respectively relative to vehicle.Each group (vehicle, or drug) had 6 mice.

What is claimed is:
 1. A compound of formula IA or IB

wherein R¹ is selected from the group consisting of H, and substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R² is selected from the group consisting of substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R³ is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; R⁴ is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; R⁵ is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; or R⁴ and R⁵, together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl or heteroaryl group; R⁶, R⁷, R⁸, and R⁹ may be the same or different, and are each independently selected from the group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R¹⁰ is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, and arylalkyl groups; and prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, hydrides thereof, or solvates thereof.
 2. The compound according to claim 1, wherein R² is selected from the group consisting of substituted and unsubstituted arylalkyl, alkenyl, heteroarylalkyl, and heterocyclylalkyl groups.
 3. The compound according to claim 1, wherein R³ is selected from the group consisting of substituted and unsubstituted cycloalkyl, alkenyl, alkyl, and aryl groups.
 4. The compound according to claim 1, wherein R⁴ and R⁵ may be the same or different and are each independently selected from the group consisting of substituted and unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups.
 5. The compound according to claim 1, wherein R⁴ and R⁵, together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl group.
 6. The compound according to claim 5, wherein R⁴ and R⁵, together with the N atom to which they are bound, form a substituted or unsubstituted saturated heterocyclyl group comprising at least one heteroatom selected from the group consisting of O, S, and N in addition to the N atom to which R⁴ and R⁵ are bound.
 7. A compound of formula IIA or IIB:

wherein at least one of W, X, Y, or Z is a nitrogen atom, forming a pyridyl group; R¹ is selected from the group consisting of H, and substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R² is selected from the group consisting of substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R³ is selected from the group consisting of H and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; R⁴ is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; R⁵ is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; or R⁴ and R⁵, together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl or heteroaryl group; R⁶, R⁷, R⁸, and R⁹ may be the same or different, and are each independently selected from the group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; wherein R⁶ may be absent if W is a nitrogen atom; wherein R⁷ may be absent if X is a nitrogen atom; wherein R⁸ may be absent if Z is a nitrogen atom; wherein R⁹ may be absent if Y is a nitrogen atom; R¹⁰ is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, and arylalkyl groups; prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, hydrides thereof, or solvates thereof.
 8. The compound according to claim 7, wherein R² is selected from the group consisting of substituted and unsubstituted arylalkyl, alkenyl, heteroarylalkyl, and heterocyclylalkyl groups.
 9. The compound according to claim 7, wherein R³ is selected from the group consisting of substituted and unsubstituted cycloalkyl, alkenyl, alkyl, and aryl groups.
 10. The compound according to claim 7, wherein R⁴ and R⁵ may be the same or different and are each independently selected from the group consisting of substituted and unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups.
 11. The compound according to claim 7, wherein R⁴ and R⁵, together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl group.
 12. The compound according to claim 11, wherein R⁴ and R⁵, together with the N atom to which they are bound, form a substituted or unsubstituted saturated heterocyclyl group comprising at least one heteroatom selected from the group consisting of O, S, and N in addition to the N atom to which R⁴ and R⁵ are bound.
 13. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
 14. A method of treating an MC4-R mediated disease, comprising administering to a subject in need thereof, the compound according to claim
 1. 15. The method according to claim 14, wherein the disease is obesity or type II diabetes.
 16. A composition comprising the compound according to claim 7 and a pharmaceutically acceptable carrier.
 17. A method of treating an MC4-R mediated disease, comprising administering to a subject in need thereof, the compound according to claim
 7. 18. The method according to claim 17, wherein the disease is obesity or type II diabetes. 